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]

Variant: NM_000527.5(LDLR):c.1243G>C (p.Asp415His)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585371

251748 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 2031df77-308b-4d89-9625-dff44bf8c877

Approved on: 2023-06-23

Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.1243G>C

NM_000527.5(LDLR):c.1243G>C (p.Asp415His)

NC_000019.10:g.11113334G>C

CM000681.2:g.11113334G>C

NC_000019.9:g.11224010G>C

CM000681.1:g.11224010G>C

NC_000019.8:g.11085010G>C

NG_009060.1:g.28954G>C

ENST00000252444.10:c.1501G>C

ENST00000559340.2:c.1243G>C

ENST00000560467.2:c.1123G>C

ENST00000558518.6:c.1243G>C

ENST00000252444.9:c.1497G>C

ENST00000455727.6:c.739G>C

ENST00000535915.5:c.1120G>C

ENST00000545707.5:c.862G>C

ENST00000557933.5:c.1243G>C

ENST00000558013.5:c.1243G>C

ENST00000558518.5:c.1243G>C

ENST00000560173.1:n.242G>C

ENST00000560467.1:c.723G>C

NM_000527.4:c.1243G>C

NM_001195798.1:c.1243G>C

NM_001195799.1:c.1120G>C

NM_001195800.1:c.739G>C

NM_001195803.1:c.862G>C

NM_001195798.2:c.1243G>C

NM_001195799.2:c.1120G>C

NM_001195800.2:c.739G>C

NM_001195803.2:c.862G>C

Likely Pathogenic

PP4 PP3 PM3 PM2

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1243G>C (p.Asp415His) variant is classified as Likely Pathogenic, for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.805. PP4: Variant meets PM2 and is identified in at least 1 index case fulfilling criteria for FH from PMID 11810272 (Fouchier et al., 2001), The Netherlands. PM3: Variant meets PM2 and was identified in an index case with homozygous FH phenotype (LDL-c 893 mg/dL) and LDLR variant (Cys143*) in trans, classified as Pathogenic by these guidelines, from PMID 26894473 (Sanna et al., 2016), Belgium.

PP4

- PP4: Variant meets PM2 and is identified in at least 1 index case fulfilling Simon Broome criteria for definite or possible FH phenotype from PMID:11810272.

PP3

- PP3: REVEL = 0.805. It is above 0.75, so PP3 is met.

PM3

- PM3: Variant meets PM2 and was identified in an index case with homozygous FH phenotype (LDL-c 893 mg/dL) and LDLR variant (Cys143*) in trans, classified as Pathogenic by these guidelines, from lab PMID: 26894473.

PM2

- PM2: This variant is absent from gnomAD (gnomAD v2.1.1).

PM5

NM_000527.5(LDLR):c.1244A>G (p.Asp415Gly) (ClinVar ID: 251749) considered as Likely Pathogenic by these guidelines. NM_000527.5(LDLR):c.1244A>T (p.Asp415Val) (ClinVar ID: 251750) considered as VUS by these guidelines.

Curation History

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