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.937T>C (p.Cys313Arg)

CA10585207

251537 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
UUID: f83f99f0-226d-4d9d-9eb2-e32d2fbe6149
Approved on: 2023-04-28
Published on: 2023-04-30

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
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Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 5
PP4 PP3 PM1 PM2 PS4_Supporting
Not Met criteria codes 2
PS3 PM5

Evidence Links 0

Expert Panel

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.
Met criteria codes
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.
PM1
Variant meets PM2 and is one of the cysteine residues listed involving disulfide bone formation.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
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.
Not Met criteria codes
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.
Curation History
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