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]

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Variant: NM_000527.5(LDLR):c.920A>G (p.Asp307Gly)

CA404081052

523725 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 018861b5-2240-4a88-98f5-164f1a3fc184

Approved on: 2023-06-23

Published on: 2023-07-28

HGVS expressions

NM_000527.5:c.920A>G

NM_000527.5(LDLR):c.920A>G (p.Asp307Gly)

NC_000019.10:g.11107494A>G

CM000681.2:g.11107494A>G

NC_000019.9:g.11218170A>G

CM000681.1:g.11218170A>G

NC_000019.8:g.11079170A>G

NG_009060.1:g.23114A>G

ENST00000558518.6:c.920A>G

ENST00000252444.9:n.1174A>G

ENST00000455727.6:c.416A>G

ENST00000535915.5:c.797A>G

ENST00000545707.5:c.539A>G

ENST00000557933.5:c.920A>G

ENST00000558013.5:c.920A>G

ENST00000558518.5:c.920A>G

ENST00000558528.1:n.435A>G

ENST00000560467.1:n.520A>G

NM_000527.4:c.920A>G

NM_001195798.1:c.920A>G

NM_001195799.1:c.797A>G

NM_001195800.1:c.416A>G

NM_001195803.1:c.539A>G

NM_001195798.2:c.920A>G

NM_001195799.2:c.797A>G

NM_001195800.2:c.416A>G

NM_001195803.2:c.539A>G

Likely Pathogenic

PP4 PP3 PM2 PM3 PS4_Supporting

PM5

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 NM_000527.5(LDLR):c.920A>G (p.Asp307Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PP3, PP4, and PS4_Supporting 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). PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype and homozygous for the NM_000527.5(LDLR):c.920A>G (p.Asp307Gly) variant (PMID: 28502510). PP3: REVEL = 0.985. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definite criteria for FH after alternative causes of high cholesterol were excluded (M. Arca Lab, Research Lab of Molecular Genetics of Lipid Metabolism, Department of Translational and Precision Medicine). PS4_Supporting: Variant meets PM2 and is identified in at least three index cases who fulfills SB definite criteria for FH after alternative causes of high cholesterol were excluded (PMID: 28502510, M. Arca Lab, Research Lab of Molecular Genetics of Lipid Metabolism, Department of Translational and Precision Medicine).

PP4

Variant meets PM2 and is identified in at least 1 index case who fulfills SB definite criteria for FH after alternative causes of high cholesterol were excluded (M. Arca Lab, Research Lab of Molecular Genetics of Lipid Metabolism, Department of Translational and Precision Medicine)

PP3

REVEL = 0.985.

PM2

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

PM3

Variant meets PM2 and is identified in an index case with homozygous FH phenotype and homozygous for the NM_000527.5(LDLR):c.920A>G (p.Asp307Gly) variant (PMID: 28502510).

PS4_Supporting

Variant meets PM2 and is identified in at least three index cases who fulfills SB definite criteria for FH after alternative causes of high cholesterol were excluded (PMID: 28502510, M. Arca Lab, Research Lab of Molecular Genetics of Lipid Metabolism, Department of Translational and Precision Medicine).

PM5

1 other missense variant in the same codon: NM_000527.5(LDLR):c.919G>A (p.Asp307Asn) - Pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.

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