Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala)

CA10585287

251645 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 3cb94032-782f-4eb2-b705-a27547228f7e

HGVS expressions

NM_000527.5:c.1067A>C

NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala)

NC_000019.10:g.11111520A>C

CM000681.2:g.11111520A>C

NC_000019.9:g.11222196A>C

CM000681.1:g.11222196A>C

NC_000019.8:g.11083196A>C

NG_009060.1:g.27140A>C

ENST00000558518.6:c.1067A>C

ENST00000252444.9:n.1321A>C

ENST00000455727.6:c.563A>C

ENST00000535915.5:c.944A>C

ENST00000545707.5:c.686A>C

ENST00000557933.5:c.1067A>C

ENST00000558013.5:c.1067A>C

ENST00000558518.5:c.1067A>C

ENST00000560173.1:n.66A>C

ENST00000560467.1:n.547A>C

NM_000527.4:c.1067A>C

NM_001195798.1:c.1067A>C

NM_001195799.1:c.944A>C

NM_001195800.1:c.563A>C

NM_001195803.1:c.686A>C

NM_001195798.2:c.1067A>C

NM_001195799.2:c.944A>C

NM_001195800.2:c.563A>C

NM_001195803.2:c.686A>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PP4 PP1 PP3 PM2 PM5

PS4

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The variant NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala) is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP1, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP1 - variant segregates with FH phenotype in 2 informative meiosis in 1 family from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obeste et des Dyslipidemies (APHP Sorbonne Univeristie Hopitalde la Pitie-Salpetriere): 2 affected family members have the variant. PP3 - REVEL=0.947 PP4 - Variant meets PM2 and is identified in at least 1 index case meeting clinical diagnostic criteria for FH, after alternative causes of high cholesterol were excluded. PM5: 4 other missense variants in the same codon: 1) NM_000527.5(LDLR):c.1066G>T (p.Asp356Tyr) (ClinVar ID 226345) - Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1066G>C (p.Asp356His) (ClinVar ID 251644) - Likely Pathogenic by these guidelines. 3) NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn) (ClinVar ID 251643) - Unknown Significance by these guidelines. 4) NM_000527.5(LDLR):c.1067A>T (p.Asp356Val) (ClinVar ID 440623) - Likely Pathogenic by these guidelines. There is 1 variant (p.Asp356Tyr) in the same codon classified as Pathogenic by these guidelines. So PM5 is met.

PP4

Variant meets PM2 and is identified in at least 1 index case meeting clinical diagnostic criteria for FH, after alternative causes of high cholesterol were excluded.

PP1

variant segregates with FH phenotype in 2 informative meiosis in 1 family from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obeste et des Dyslipidemies (APHP Sorbonne Univeristie Hopitalde la Pitie-Salpetriere): 2 affected family members have the variant.

PP3

REVEL=0.947

PM2

This variant is absent from gnomAD (gnomAD v2.1.1).

PM5

4 other missense variants in the same codon: 1) NM_000527.5(LDLR):c.1066G>T (p.Asp356Tyr) (ClinVar ID 226345) - Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1066G>C (p.Asp356His) (ClinVar ID 251644) - Likely Pathogenic by these guidelines. 3) NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn) (ClinVar ID 251643) - Unknown Significance by these guidelines. 4) NM_000527.5(LDLR):c.1067A>T (p.Asp356Val) (ClinVar ID 440623) - Likely Pathogenic by these guidelines. There is 1 variant (p.Asp356Tyr) in the same codon classified as Pathogenic by these guidelines. So PM5 is met.

PS4

variant meets PM2 and but is identified in only 1 index cases with DLCN criteria>=6 from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obeste et des Dyslipidemies (APHP Sorbonne Univeristie Hopitalde la Pitie-Salpetriere)

Approved on: 2023-04-28

Published on: 2023-05-01

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