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.664T>C (p.Cys222Arg)

CA044260

226332 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 89bd8cb7-28fa-4f78-9174-47bf4d529f71

HGVS expressions

NM_000527.5:c.664T>C

NM_000527.5(LDLR):c.664T>C (p.Cys222Arg)

NC_000019.10:g.11105570T>C

CM000681.2:g.11105570T>C

NC_000019.9:g.11216246T>C

CM000681.1:g.11216246T>C

NC_000019.8:g.11077246T>C

NG_009060.1:g.21190T>C

ENST00000558518.6:c.664T>C

ENST00000252444.9:n.918T>C

ENST00000455727.6:c.314-1822T>C

ENST00000535915.5:c.541T>C

ENST00000545707.5:c.314-995T>C

ENST00000557933.5:c.664T>C

ENST00000558013.5:c.664T>C

ENST00000558518.5:c.664T>C

ENST00000560467.1:n.264T>C

NM_000527.4:c.664T>C

NM_001195798.1:c.664T>C

NM_001195799.1:c.541T>C

NM_001195800.1:c.314-1822T>C

NM_001195803.1:c.314-995T>C

NM_001195798.2:c.664T>C

NM_001195799.2:c.541T>C

NM_001195800.2:c.314-1822T>C

NM_001195803.2:c.314-995T>C

Likely Pathogenic

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

PP3 PP4 PS4_Supporting PM2 PM3 PM1

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.664T>C (p.Cys222Arg) variant is classified as a Likely pathogenic variant for Familial Hypercholesterolemia by applying evidence codes PM2, PM1, PM3, PS4_supporting, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2: PopMax MAF = 0.0001098 (0.01%) in East Asian exomes (gnomAD v2.1.1) PM1: Variant meets PM2 and alters Cys222, one of the cysteine residues listed. PM3: Variant meets PM2 and is identified in two index cases with homozygous FH phenotype (LDL mmol/L = 17.9 and 14.09 respectively), PMID: 15823276 PS4_supporting: Variant meets PM2 and is identified in at least 5 index cases who fulfill SB possible/definite FH or DLCN>=6 criteria for FH from GeneDx Inc., Ambry Genetics, and the Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) PP3 : REVEL = 0.966. PP4: Variant meets PM2 and identified in at least 2 FH case from GeneDx Inc, 1 FH case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), and 1 FH case from Ambry Genetics, all of them fulfilling SB criteria for possible/definite FH or DLCN > 6.

PP3

REVEL = 0.966

PP4

Variant meets PM2 and identified in at least 2 FH case from GeneDx Inc, 1 FH case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), and 1 FH case from Ambry Genetics, all of them fulfilling SB criteria for possible/definite FH or DLCN > 6.

PS4_Supporting

Variant meets PM2 and is identified in at least 5 index cases who fulfill SB possible/definite FH or DLCN>=6 criteria for FH from GeneDx Inc., Ambry Genetics, and the Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)

PM2

PopMax MAF = 0.0001098 (0.01%) in East Asian exomes (gnomAD v2.1.1)

PM3

Variant meets PM2 and is identified in two index cases with homozygous FH phenotype (LDL mmol/L = 17.9 and 14.09 respectively), PMID: 15823276

PM1

Variant meets PM2 and alters Cys222, one of the cysteine residues listed.

Approved on: 2023-04-28

Published on: 2023-05-01

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