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.937T>C (p.Cys313Arg)

CA10585207

251537 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: f83f99f0-226d-4d9d-9eb2-e32d2fbe6149

HGVS expressions

NM_000527.5:c.937T>C

NM_000527.5(LDLR):c.937T>C (p.Cys313Arg)

NC_000019.10:g.11107511T>C

CM000681.2:g.11107511T>C

NC_000019.9:g.11218187T>C

CM000681.1:g.11218187T>C

NC_000019.8:g.11079187T>C

NG_009060.1:g.23131T>C

ENST00000558518.6:c.937T>C

ENST00000252444.9:n.1191T>C

ENST00000455727.6:c.433T>C

ENST00000535915.5:c.814T>C

ENST00000545707.5:c.556T>C

ENST00000557933.5:c.937T>C

ENST00000558013.5:c.937T>C

ENST00000558518.5:c.937T>C

ENST00000558528.1:n.452T>C

ENST00000560467.1:n.537T>C

NM_000527.4:c.937T>C

NM_001195798.1:c.937T>C

NM_001195799.1:c.814T>C

NM_001195800.1:c.433T>C

NM_001195803.1:c.556T>C

NM_001195798.2:c.937T>C

NM_001195799.2:c.814T>C

NM_001195800.2:c.433T>C

NM_001195803.2:c.556T>C

Likely Pathogenic

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

PP4 PP3 PM2 PM1 PS4_Supporting

PS3 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.937T>C (p.Cys313Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM1, PP4, 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). PP3: REVEL=0.978. PM1: Variant meets PM2 and is one of the cysteine residues listed involving disulfide bone formation. PP4: Variant meets PM2 and is identified in ˃1 index cases who fulfil criteria for FH after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases reported in PubMed: one case fulfil Simon Broome criteria for definite or possible FH in PMID 22881376, reported by Usifo et al, 2012, from British Heart Foundation Laboratories, University College London, UK; one case fulfil DLCN ≥6 in PMID 19318025 reported by Alonso et al, 2009, from Lipid Clinic, Fundacion Jimenez Diaz, Spain. PS3 not met: Functional data is not available. PM5 not met: Three other missense variants at same codon: NM_000527.5 (LDLR):c.937T>G (p.Cys313Gly), ClinVarID 251538, is classified as Uncertain significance; NM_000527.5 (LDLR):c.939C>G (p.Cys313Trp), ClinVarID 251540, is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.938G>A (p.Cys313Tyr), ClinVarID 226339, is classified as Likely Pathogenic by these guidelines, therefore PM5 is not met.

PP4

Variant meets PM2 and is identified in ˃1 index cases who fulfil criteria for FH after alternative causes of high cholesterol were excluded.

PP3

REVEL=0.978.

PM2

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

PM1

Variant meets PM2 and is one of the cysteine residues listed involving disulfide bone formation.

PS4_Supporting

Variant meets PM2 and is identified in 2 unrelated index cases reported in PubMed: one case fulfil Simon Broome criteria for definite or possible FH in PMID 22881376, reported by Usifo et al, 2012, from British Heart Foundation Laboratories, University College London, UK; one case fulfil DLCN ≥6 in PMID 19318025 reported by Alonso et al, 2009, from Lipid Clinic, Fundacion Jimenez Diaz, Spain.

PS3

Functional data is not available.

PM5

Three other missense variants at same codon: NM_000527.5 (LDLR):c.937T>G (p.Cys313Gly), ClinVarID 251538, is classified as Uncertain significance; NM_000527.5 (LDLR):c.939C>G (p.Cys313Trp), ClinVarID 251540, is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.938G>A (p.Cys313Tyr), ClinVarID 226339, is classified as Likely Pathogenic by these guidelines, therefore PM5 is not met.

Approved on: 2023-04-28

Published on: 2023-04-30

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