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.709C>T (p.Arg237Cys)

CA10585102

251421 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 0f079b07-dce5-4c8b-9a40-120dc80b5e35

HGVS expressions

NM_000527.5:c.709C>T

NM_000527.5(LDLR):c.709C>T (p.Arg237Cys)

NC_000019.10:g.11106579C>T

CM000681.2:g.11106579C>T

NC_000019.9:g.11217255C>T

CM000681.1:g.11217255C>T

NC_000019.8:g.11078255C>T

NG_009060.1:g.22199C>T

ENST00000558518.6:c.709C>T

ENST00000252444.9:n.963C>T

ENST00000455727.6:c.314-813C>T

ENST00000535915.5:c.586C>T

ENST00000545707.5:c.328C>T

ENST00000557933.5:c.709C>T

ENST00000558013.5:c.709C>T

ENST00000558518.5:c.709C>T

ENST00000558528.1:n.224C>T

ENST00000560467.1:n.309C>T

NM_000527.4:c.709C>T

NM_001195798.1:c.709C>T

NM_001195799.1:c.586C>T

NM_001195800.1:c.314-813C>T

NM_001195803.1:c.328C>T

NM_001195798.2:c.709C>T

NM_001195799.2:c.586C>T

NM_001195800.2:c.314-813C>T

NM_001195803.2:c.328C>T

Uncertain Significance

PP4 PM2 PS4_Supporting

PS1 PP3 PM5

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.709C>T (p.Arg237Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, PS4_Moderate 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 - PopMax MAF = 0.00009799 (0.01%) in South Asian exomes (gnomAD v2.1.1). PS4_Supporting - Variant meets PM2 and is reported in 3 unrelated index cases, two with possible SB criteria (PMID 20236128 and Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)), one with DLCN >= 6 criteria (PMID 30293936). PP4 - Variant meets PM2 and is reported in 3 unrelated index cases, two with possible SB criteria (PMID 20236128 and Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)), one with DLCN >= 6 criteria (PMID 30293936).

PP4

Variant meets PM2 and is reported in 3 unrelated index cases, two with possible SB criteria (PMID 20236128 and Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)), one with DLCN >= 6 criteria (PMID 30293936).

PM2

PopMax MAF = 0.00009799 (0.01%) in South Asian exomes (gnomAD v2.1.1).

PS4_Supporting

PS1

no other missense variants at same codon with same aa change

PP3

REVEL = 0.743. It is not above 0.75, plicing evaluation required. There is no functional data on splicing available. Variant is exonic, and at least 50 bp upstream from canonical donor site but does not create an AG, so PP3 is not met.

PM5

There is one other missense variant in the same codon NM_000527.5(LDLR):c.710G>A (p.Arg237His). It is considered as Uncertain significance - insufficient evidence by this guidelines. PM5 is not met.

Approved on: 2022-04-30

Published on: 2022-04-30

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