Submissions for variant NM_000527.5(LDLR):c.1955T>C (p.Met652Thr)

dbSNP: rs875989936

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211590	SCV002817176	likely pathogenic	Hypercholesterolemia, familial, 1	2022-08-29	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP1_Moderate and 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 follow: PM2_ Met : Allele frequency is 0.00005 (18394 alleles) in the East Asian subpopulation in GnomAD (gnomAD v2.1.1). PP4_Met : 2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA - as defined by DLCN>6 and 1 from PMID: 20236128 as defined by Simon Broome score = definite). PS4_Supporting: 2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA -with DLCN>6 and 1 from PMID: 20236128 with Simon Broome score = definite) and 1 case with untreated LDL-C=348 (Ambry Genetics). PMID:20829525 1 carrier was identified but the FH phenotype was evaluated only considering total and LDL-cholesterol levels above the 95 th percentile when compared with a sex- and age-matched French population. I will not consider this patient. PMID:22883975 1 carrier with clinical FH defined by DLCN score was reported. However, it is impossible to understand if the patient carrying the variant has a DLCN>6. I will not consider this patient. PMID: 28964736 1 carrier with clinical FH was reported in the cohort of ALTERNATIVE study which did not have a recorded diagnosis of FH, as they had very high baseline LDL-C levels (>5.0 mmol/L, ∼193 mg/dL).No data on FH its FC classification is reported. I will not consider this patient. PP1_Strong : Variant segregates with phenotype in 5 relatives in 1 family. (8 informative meiosis)
LDLR-LOVD, British Heart Foundation	RCV000211590	SCV000295774	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000211590	SCV000503437	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 / Other mutation at same codon/Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211590	SCV000583911	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775082	SCV000627024	pathogenic	Familial hypercholesterolemia	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 652 of the LDLR protein (p.Met652Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 28964736; Invitae). ClinVar contains an entry for this variant (Variation ID: 226382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775082	SCV000909186	uncertain significance	Familial hypercholesterolemia	2020-03-26	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Met631Thr in the mature protein) replaces methionine with threonine at codon 652 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 20236128, 20809525, 22883975, 28964736). It has been shown that this variant segregates with disease in one family (Al-Olabi et al 2019). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	RCV000775082	SCV001482447	uncertain significance	Familial hypercholesterolemia		criteria provided, single submitter	research
Ambry Genetics	RCV002415887	SCV002718365	likely pathogenic	Cardiovascular phenotype	2024-03-19	criteria provided, single submitter	clinical testing	The p.M652T variant (also known as c.1955T>C), located in coding exon 13 of the LDLR gene, results from a T to C substitution at nucleotide position 1955. The methionine at codon 652 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH) (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Taylor A et al. Clin Genet, 2010 Jun;77:572-80; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Defesche JC et al. J Clin Lipidol, 2017 Sep;11:1338-1346.e7; Ajufo E et al. Genet Med, 2021 Sep;23:1697-1704). (Meshkov A et al. Genes (Basel), 2021 Jan;12; Ambry internal data). Internal structural analysis indicates this variant to be structurally disruptive (Rudenko G et al. Science. 2002 Dec;298(5602):2353-8). Additionally, an in vitro assay showed this alteration had a reduction of LDL uptake (Larrea-Sebal A et al. JACC Basic Transl Sci, 2021 Nov;6:815-827). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211590	SCV000268651	pathogenic	Hypercholesterolemia, familial, 1	2008-06-25	no assertion criteria provided	clinical testing