ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.265T>C (p.Cys89Arg)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237985 SCV002506374 likely pathogenic Hypercholesterolemia, familial, 1 2022-03-25 reviewed by expert panel curation The NM_000527.5(LDLR):c.265T>C (p.Cys89Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PM3, PS4_Supporting, PP1, PP3 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: PM1 - Variant meets PM2 and alters Cys89, one of the cysteine residues listed, so PM1 is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 18.05 mmol/L) and LDLR variant c.1775G>A/p.(Gly592Glu), classified as Pathogenic by these guidelines, in trans, from ltaly (PMID: 9974426), so PM3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases: 1 index case with possible FH (Simon-Broome criteria) from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, at least 1 index case with definite heterozygous FH from The Netherlands (PMID: 16250003), 1 index case fulfilling MedPed criteria for FH from Spain (PMID: 16627557), 2 index cases fulfilling WHO criteria for FH from Poland (PMID: 20145306), so PS4_Supporting is Met. PP1 - Variant segregates with FH phenotype in 3 informative meiosis from 1 family from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 2 affected family members have the variant and 1 non-affected family member does not have the variant, so PP1 is Met. PP3 - REVEL = 0.973. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 5 unrelated index cases fulfilling clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met.
LDLR-LOVD, British Heart Foundation RCV000237985 SCV000294565 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237985 SCV000322883 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/208 non-FH alleles
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237985 SCV000588492 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Revvity Omics, Revvity RCV000237985 SCV003819465 pathogenic Hypercholesterolemia, familial, 1 2022-11-14 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237985 SCV000606055 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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