Submissions for variant NM_000527.5(LDLR):c.2106G>A (p.Met702Ile)

gnomAD frequency: 0.00011  dbSNP: rs140731590

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000352480	SCV005375288	uncertain significance	Hypercholesterolemia, familial, 1	2024-08-30	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.2106G>A (p.Met702Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia as no ACMG/AMP evidence codes were met as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on August 30, 2024.
Illumina Laboratory Services, Illumina	RCV000352480	SCV000410541	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000352480	SCV000503464	likely benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1/Software predictions: Conflicting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775088	SCV000752436	likely benign	Familial hypercholesterolemia	2025-01-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712213	SCV000842651	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775088	SCV000909192	likely benign	Familial hypercholesterolemia	2020-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000712213	SCV001134258	uncertain significance	not provided	2024-11-07	criteria provided, single submitter	clinical testing	The LDLR c.2106G>A (p.Met702Ile) variant has been reported in the published literature in individuals with autosomal dominant hypercholesterolemia (PMID: 26802169 (2016)), myocardial infarction (PMID: 25487149 (2015)), high LDL-C (PMID: 24507775 (2014)) as well as reportedly healthy individuals (PMID: 25487149 (2015), 30487145 (2018)). The frequency of this variant in the general population, 0.0027 (28/10366 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV000712213	SCV002567422	uncertain significance	not provided	2022-07-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with high LDL-C levels and/or FH in the published literature (Lange et al., 2014; Wintjens et al., 2016; Dron et al., 2020); This variant is associated with the following publications: (PMID: 26802169, 25487149, 30487145, 24507775, 32041611)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330641	SCV004039147	likely benign	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2106G>A (p.Met702Ile) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250972 control chromosomes (gnomAD), predominantly at a frequency of 0.0026 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.2106G>A has been reported in the literature in individuals affected with Hypercholesterolemia (Lange_2014, Wintjens_2016), Dyslipidemia (Dron_2020), and in an individual with Myocardial Infarction (Do_2015) without evidence for causality. The variant was also reported in control individuals (Do_2015, Rego_2018). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25487149, 32041611, 24507775, 30487145, 26802169). Seven ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000712213	SCV004224560	uncertain significance	not provided	2022-06-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004639218	SCV005135980	uncertain significance	Cardiovascular phenotype	2024-06-19	criteria provided, single submitter	clinical testing	The p.M702I variant (also known as c.2106G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2106. The methionine at codon 702 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in association with familial hypercholesterolemia (FH), but has also been seen in ostensibly healthy cohorts (Lange LA et al. Am J Hum Genet, 2014 Feb;94:233-45; Do R et al. Nature, 2015 Feb;518:102-6; Wintjens R et al. J Lipid Res, 2016 Mar;57:482-91; Rego S et al. Cold Spring Harb Mol Case Stud, 2018 Dec;4:). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000352480	SCV000606600	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research