Others an der Albert-Ludwigs-Universität Freiburg | Karteikarten & Zusammenfassungen

Lernmaterialien für Others an der Albert-Ludwigs-Universität Freiburg

Greife auf kostenlose Karteikarten, Zusammenfassungen, Übungsaufgaben und Altklausuren für deinen Others Kurs an der Albert-Ludwigs-Universität Freiburg zu.

TESTE DEIN WISSEN

ACMG/AMP 2015 criteria for classifying benign variants


Lösung anzeigen
TESTE DEIN WISSEN

BA (Stand-alone):

    1. Allele frequency is >5% in gnomAD/ExAC

BS: 

    1. Allele frequency is greater than expected for disorder

    2. Observed in healthy adult (for full penetrant, early-onset disorder)

    3. In vitro or in vivo studies show no damaging effect

    4. Lack of segregation in affected family members

BP:

    1. Missense in gene where truncating variants cause disease

    2. In trans with pathogenic variant for AD disorder

    3. In silico/computer algorithms (SIFT, PROVEAN) predict no effect

    4. Variant found in individual with alternate molecular basis for disease

    5. Reputable source recently reports the variant as benign

    6. Silent variant w/o predicted splice effect and w/o high conservation

Lösung ausblenden
TESTE DEIN WISSEN

ACMG/AMP 2015 rules for combining criteria to classify sequence variants

Lösung anzeigen
TESTE DEIN WISSEN

Pathogenic: 

1. 

  • 1PVS + ≥1PS
  • 1PVS + ≥2PM
  • 1PVS + 1PM + 1PP
  • 1PVS + ≥2PP

2. 

  • ≥2PS 

3. 

  • 1PS + ≥3PM
  • 1PS + 2PM + ≥2PP
  • 1PS + 1PM + ≥4 PP

Likely pathogenic:

    1. 1PVS + 1PM

    2. 1PS + 1-2PM

    3. 1PS + ≥2PP

    4. ≥3PM

    5. 2PM + ≥2PP

    6. 1PM + ≥4PP

Benign: 

    1. 1BA

    2. ≥2BS

Likely benign:

    1. 1BS + 1BP

    2. ≥2BP

VUS:    

    1. Criteria above are not met

    2. Criteria are contradictory

Lösung ausblenden
TESTE DEIN WISSEN

First trimester screen (9-13 weeks)

Lösung anzeigen
TESTE DEIN WISSEN

Evaluation

T21

T18

T13

NT (Nuchal translucency)

high

high

high

HCG (Human chorionic gonatropin)

high

low

low

PAPP-A (pregnancy-associated plasma protein A

low

low

low

Lösung ausblenden
TESTE DEIN WISSEN

Second trimester screen/Quad screen (15-20 weeks)

Lösung anzeigen
TESTE DEIN WISSEN

Evaluation

T21

T18

T13

NTD

AFP (Alpha-fetoprotein)

low

low

low

high

µ-E3 (Estriol)

low

low

low

low

HCG (Human chorionic gonatropin)

high

low

low

low

Inhibin A

high

low

normal

normal

Lösung ausblenden
TESTE DEIN WISSEN

HLA-B*57:01

Lösung anzeigen
TESTE DEIN WISSEN
  • Abcavir (Ziagen; antiviral drug, i.e. HIV)
  • binds to HLA-B*57:01 and changes its binding affinity --> presentation of self-antigens
  • Inflammation and skin rash (Steve-Johnson Syndrome/Toxic Epidermal Necrolysis)
  • testing is recommended befire Abcavir treatment
  • use different drug if HLA-B*57:01 genotype is present (6% Caucasians, 2-3% African Americans)
Lösung ausblenden
TESTE DEIN WISSEN

HLA-B*15:02

Lösung anzeigen
TESTE DEIN WISSEN
  • Carbamazepine (phenytoin; antiseizure drug)
  • hypersensitivity if HLA-B*15:02 allele is present (Asians) --> Steve-Johnson Syndrome/Toxic Epidermal Necrolysis
  • use different drug
Lösung ausblenden
TESTE DEIN WISSEN

HLA-B*58:01

Lösung anzeigen
TESTE DEIN WISSEN
  • Allopurinol (brand names Zyloprim, Aloprim; gout treatment)
  • associated with severe cutaneous adverse reaction (SCAR)
Lösung ausblenden
TESTE DEIN WISSEN

VKORC1


Lösung anzeigen
TESTE DEIN WISSEN
  • Warfarin is an oral anticoagulant used for treatment of DVT --> acts by inhibiting synthesis of vitamin K-dependent clotting factor
  • VKORC1 recycles vitamin K --> important for clotting
  • recycled vitamin K is needed for functional clotting; if not enough recycled vitamin K is available --> bleeding 
  • Warfarin inhibits VKORC1 --> reduced vitamin K recycling --> reduced clotting (but also: reduced bone formation in embryo)
  • VKORC1, c.-1639G>A --> increased inhibition by warfarin --> clotting is too much reduced/bleeding --> use lower starting dose for individuals with c.-1639A/A
  • FDA drug label states that CYP2C9 and VKORC1 genotypes can assist in initial dosage choice
Lösung ausblenden
TESTE DEIN WISSEN

CYP2C9

Lösung anzeigen
TESTE DEIN WISSEN
  • Warfarin is an oral anticoagulant used for treatment of DVT --> acts by inhibiting synthesis of vitamin K-dependent clotting factor
  • CYP2C9 metabolizes S-warfarin (the more active isomer of warfarin)
  • CYP2C9*2 (p.Arg144Cys) and CYP2C9*3 (p.Ile359Leu) --> metabolize S-warfarin slower -->   lower starting dose needed
  • individuals with CYP2C9*2/*2 and normal dose of S-warfarin are prone to bleeding (excessive anticoagulation because S-warfarin is not metabolized)
  • CYP2C9*17 --> ultra-rapid metabolizer --> higher dose requirements
  • FDA drug label states that CYP2C9 and VKORC1 genotypes can assist in initial dosage choice
Lösung ausblenden
TESTE DEIN WISSEN

CYP2C19

Lösung anzeigen
TESTE DEIN WISSEN
  • Clopidrogel (Plavix) is a platelet inhibitor --> less clotting (reduces risk of myocardial infarction and stroke)
  • Clopidrogel is pro-drug --> gets activated by CYP2C19
  • CYP2C19*2, *3 and *4 are LoF alleles; HOMs are PM
  • CYP2C19*2/*2 is common: 4% Europeans, 15% Asians
  • PM (i.e. CYP2C19*2/CYP2C19*2) --> clopidrogel cannot be activated —> use different drug
  • URM (i.e. CYP2C19*17)


Lösung ausblenden
TESTE DEIN WISSEN

CYP2D6


Lösung anzeigen
TESTE DEIN WISSEN
  • Categories: 
    • NM: normal/normal or normal/reduced = N/N or N/R
    • IM: normal/non-function or reduced/reduced = N/0 or R/R
    • PM: non-function/non-function = 0/0 (i.e. HOM for CYP2D6*3/4/5/6)
    • URM: more than 2x nl = >N/N (i.e. CYP2D6*1x2/CYP2D6*2)
  • Important for metabolism of beta blockers (i.e. metoprolol), risperidone, codeine, and tamoxifen
  • 1. Beta blocker: 
    • PMs (6-8% of Caucasians) --> high levels of drug in blood --> risk for bradycardia/hypotension —> decrease dosage
  • 2. Risperidone: 
    • PM have higher dose of risperidone in their blood --> decrease dosage
  • 3. Codeine:

    • Codeine is pro-drug

    • ~15% gets activated by CYP2D6 to morphine (active compound); 80% gets inactivated and secreted

    • URM (i.e. CYP2D6*1 x 3): risk for morphine overdose!; risk for high morphine dose in breast milk --> use different drug!

    • PM (i.e. CYP2D6*3 HOM): no sufficient pain relieve --> use higher dose

  • 4. Tamoxifen:

    • pro-drug —> in liver to endoxifen

    • UM (*1/*1xN, *1/*2xN, *2/*2xN) should get lower drug dose

Lösung ausblenden
TESTE DEIN WISSEN

ACMG/AMP 2015 criteria for classifying pathogenic variants

Lösung anzeigen
TESTE DEIN WISSEN

PVS: 

    1. Null variants (LoF is known mechanism)

PS:

    1. Same amino acid chance as already shown

    2. De novo (pat and mat confirmed)

    3. In vitro or in vivo studies

    4. Higher F in affected ind. (case control studies; OR > 5.0)

PM:     

    1. In mutational hotspot or functional domain

    2. Absent from controls (ExAC/GnomAD)

    3. In trans with pathogenic variant (for AR disorders)

    4. Protein length changes (in-frame/STOP loss)

    5. Novel missense change at pathogenic different missense change

    6. Assumed de novo (pat and mat confirmed not confirmed)

PP: 

    1. Co-segregation with disease in family in know disease gene

    2. Missense in gene with low rate of benign missense and missense disease mechanism

    3. In silico/computer algorithms predict damaging

    4. Phenotype is highly specific for single gene disorder

    5. Reputable source recently reports the variant pathogenic

Lösung ausblenden
  • 92001 Karteikarten
  • 1240 Studierende
  • 17 Lernmaterialien

Beispielhafte Karteikarten für deinen Others Kurs an der Albert-Ludwigs-Universität Freiburg - von Kommilitonen auf StudySmarter erstellt!

Q:

ACMG/AMP 2015 criteria for classifying benign variants


A:

BA (Stand-alone):

    1. Allele frequency is >5% in gnomAD/ExAC

BS: 

    1. Allele frequency is greater than expected for disorder

    2. Observed in healthy adult (for full penetrant, early-onset disorder)

    3. In vitro or in vivo studies show no damaging effect

    4. Lack of segregation in affected family members

BP:

    1. Missense in gene where truncating variants cause disease

    2. In trans with pathogenic variant for AD disorder

    3. In silico/computer algorithms (SIFT, PROVEAN) predict no effect

    4. Variant found in individual with alternate molecular basis for disease

    5. Reputable source recently reports the variant as benign

    6. Silent variant w/o predicted splice effect and w/o high conservation

Q:

ACMG/AMP 2015 rules for combining criteria to classify sequence variants

A:

Pathogenic: 

1. 

  • 1PVS + ≥1PS
  • 1PVS + ≥2PM
  • 1PVS + 1PM + 1PP
  • 1PVS + ≥2PP

2. 

  • ≥2PS 

3. 

  • 1PS + ≥3PM
  • 1PS + 2PM + ≥2PP
  • 1PS + 1PM + ≥4 PP

Likely pathogenic:

    1. 1PVS + 1PM

    2. 1PS + 1-2PM

    3. 1PS + ≥2PP

    4. ≥3PM

    5. 2PM + ≥2PP

    6. 1PM + ≥4PP

Benign: 

    1. 1BA

    2. ≥2BS

Likely benign:

    1. 1BS + 1BP

    2. ≥2BP

VUS:    

    1. Criteria above are not met

    2. Criteria are contradictory

Q:

First trimester screen (9-13 weeks)

A:

Evaluation

T21

T18

T13

NT (Nuchal translucency)

high

high

high

HCG (Human chorionic gonatropin)

high

low

low

PAPP-A (pregnancy-associated plasma protein A

low

low

low

Q:

Second trimester screen/Quad screen (15-20 weeks)

A:

Evaluation

T21

T18

T13

NTD

AFP (Alpha-fetoprotein)

low

low

low

high

µ-E3 (Estriol)

low

low

low

low

HCG (Human chorionic gonatropin)

high

low

low

low

Inhibin A

high

low

normal

normal

Q:

HLA-B*57:01

A:
  • Abcavir (Ziagen; antiviral drug, i.e. HIV)
  • binds to HLA-B*57:01 and changes its binding affinity --> presentation of self-antigens
  • Inflammation and skin rash (Steve-Johnson Syndrome/Toxic Epidermal Necrolysis)
  • testing is recommended befire Abcavir treatment
  • use different drug if HLA-B*57:01 genotype is present (6% Caucasians, 2-3% African Americans)
Mehr Karteikarten anzeigen
Q:

HLA-B*15:02

A:
  • Carbamazepine (phenytoin; antiseizure drug)
  • hypersensitivity if HLA-B*15:02 allele is present (Asians) --> Steve-Johnson Syndrome/Toxic Epidermal Necrolysis
  • use different drug
Q:

HLA-B*58:01

A:
  • Allopurinol (brand names Zyloprim, Aloprim; gout treatment)
  • associated with severe cutaneous adverse reaction (SCAR)
Q:

VKORC1


A:
  • Warfarin is an oral anticoagulant used for treatment of DVT --> acts by inhibiting synthesis of vitamin K-dependent clotting factor
  • VKORC1 recycles vitamin K --> important for clotting
  • recycled vitamin K is needed for functional clotting; if not enough recycled vitamin K is available --> bleeding 
  • Warfarin inhibits VKORC1 --> reduced vitamin K recycling --> reduced clotting (but also: reduced bone formation in embryo)
  • VKORC1, c.-1639G>A --> increased inhibition by warfarin --> clotting is too much reduced/bleeding --> use lower starting dose for individuals with c.-1639A/A
  • FDA drug label states that CYP2C9 and VKORC1 genotypes can assist in initial dosage choice
Q:

CYP2C9

A:
  • Warfarin is an oral anticoagulant used for treatment of DVT --> acts by inhibiting synthesis of vitamin K-dependent clotting factor
  • CYP2C9 metabolizes S-warfarin (the more active isomer of warfarin)
  • CYP2C9*2 (p.Arg144Cys) and CYP2C9*3 (p.Ile359Leu) --> metabolize S-warfarin slower -->   lower starting dose needed
  • individuals with CYP2C9*2/*2 and normal dose of S-warfarin are prone to bleeding (excessive anticoagulation because S-warfarin is not metabolized)
  • CYP2C9*17 --> ultra-rapid metabolizer --> higher dose requirements
  • FDA drug label states that CYP2C9 and VKORC1 genotypes can assist in initial dosage choice
Q:

CYP2C19

A:
  • Clopidrogel (Plavix) is a platelet inhibitor --> less clotting (reduces risk of myocardial infarction and stroke)
  • Clopidrogel is pro-drug --> gets activated by CYP2C19
  • CYP2C19*2, *3 and *4 are LoF alleles; HOMs are PM
  • CYP2C19*2/*2 is common: 4% Europeans, 15% Asians
  • PM (i.e. CYP2C19*2/CYP2C19*2) --> clopidrogel cannot be activated —> use different drug
  • URM (i.e. CYP2C19*17)


Q:

CYP2D6


A:
  • Categories: 
    • NM: normal/normal or normal/reduced = N/N or N/R
    • IM: normal/non-function or reduced/reduced = N/0 or R/R
    • PM: non-function/non-function = 0/0 (i.e. HOM for CYP2D6*3/4/5/6)
    • URM: more than 2x nl = >N/N (i.e. CYP2D6*1x2/CYP2D6*2)
  • Important for metabolism of beta blockers (i.e. metoprolol), risperidone, codeine, and tamoxifen
  • 1. Beta blocker: 
    • PMs (6-8% of Caucasians) --> high levels of drug in blood --> risk for bradycardia/hypotension —> decrease dosage
  • 2. Risperidone: 
    • PM have higher dose of risperidone in their blood --> decrease dosage
  • 3. Codeine:

    • Codeine is pro-drug

    • ~15% gets activated by CYP2D6 to morphine (active compound); 80% gets inactivated and secreted

    • URM (i.e. CYP2D6*1 x 3): risk for morphine overdose!; risk for high morphine dose in breast milk --> use different drug!

    • PM (i.e. CYP2D6*3 HOM): no sufficient pain relieve --> use higher dose

  • 4. Tamoxifen:

    • pro-drug —> in liver to endoxifen

    • UM (*1/*1xN, *1/*2xN, *2/*2xN) should get lower drug dose

Q:

ACMG/AMP 2015 criteria for classifying pathogenic variants

A:

PVS: 

    1. Null variants (LoF is known mechanism)

PS:

    1. Same amino acid chance as already shown

    2. De novo (pat and mat confirmed)

    3. In vitro or in vivo studies

    4. Higher F in affected ind. (case control studies; OR > 5.0)

PM:     

    1. In mutational hotspot or functional domain

    2. Absent from controls (ExAC/GnomAD)

    3. In trans with pathogenic variant (for AR disorders)

    4. Protein length changes (in-frame/STOP loss)

    5. Novel missense change at pathogenic different missense change

    6. Assumed de novo (pat and mat confirmed not confirmed)

PP: 

    1. Co-segregation with disease in family in know disease gene

    2. Missense in gene with low rate of benign missense and missense disease mechanism

    3. In silico/computer algorithms predict damaging

    4. Phenotype is highly specific for single gene disorder

    5. Reputable source recently reports the variant pathogenic

Others

Erstelle und finde Lernmaterialien auf StudySmarter.

Greife kostenlos auf tausende geteilte Karteikarten, Zusammenfassungen, Altklausuren und mehr zu.

Jetzt loslegen

Das sind die beliebtesten Others Kurse im gesamten StudySmarter Universum

Tschechisch other

Masaryk University

Zum Kurs
Hydrotherapie

Medizinische Hochschule Brandenburg Theodor Fontane

Zum Kurs

Die all-in-one Lernapp für Studierende

Greife auf Millionen geteilter Lernmaterialien der StudySmarter Community zu
Kostenlos anmelden Others
Erstelle Karteikarten und Zusammenfassungen mit den StudySmarter Tools
Kostenlos loslegen Others