Submissions for variant NM_000527.5(LDLR):c.2575G>A (p.Val859Met)

gnomAD frequency: 0.00004  dbSNP: rs202049029

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237470	SCV001960947	likely benign	Hypercholesterolemia, familial, 1	2021-06-24	reviewed by expert panel	curation	NM_000527.5(LDLR):c.2575G>A (p.Val859Met) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (BS3, BP4, and PM2, PP4 and PS4_Supporting) 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: BS3 - PMID: 25386756 - Level 1 assay - Expression >90%, uptake 90%, degradation of 125I-LDL 90%. BP4 - REVEL: 0,209. Score is below 0,5. Splicing predictors - negative. so BP4 is met. PM2 - PopMa MAF = 0.0001629 (0.01629%) in 'Other' (gnomAD v2.1.1). PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill Simon-Broome criteria for FH (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge who fulfill Simon-Broome criteria for FH. Variant has 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Moderate and 1 Supporting evidence codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign
LDLR-LOVD, British Heart Foundation	RCV000237470	SCV000296039	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237470	SCV000323018	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles
Color Diagnostics, LLC DBA Color Health	RCV000771548	SCV000904110	likely benign	Familial hypercholesterolemia	2023-02-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000237470	SCV001286500	uncertain significance	Hypercholesterolemia, familial, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001589203	SCV001825118	likely benign	not provided	2018-09-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25741862, 29874871, 25781017, 25647241, 25386756, 17765246, 25487149)
Ambry Genetics	RCV002450754	SCV002738931	uncertain significance	Cardiovascular phenotype	2019-02-20	criteria provided, single submitter	clinical testing	The p.V859M variant (also known as c.2575G>A), located in coding exon 18 of the LDLR gene, results from a G to A substitution at nucleotide position 2575. The valine at codon 859 is replaced by methionine, an amino acid with highly similar properties. This variant (also referred to as V838M) has been detected in a proband described as having possible familial hypercholesterolemia; however, segregation with disease in the family was unclear (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Silva S et al. Atherosclerosis, 2012 Nov;225:128-34). This variant has also been detected in a myocardial infarction cohort in association with high LDL; however, details were limited (Do R et al. Nature, 2015 Feb;518:102-6; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This variant has also been detected in an exome cohort (Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45). Experimental studies have indicated that cells expressing this variant functioned similarly to wild type (Silva S et al. Atherosclerosis, 2012 Nov;225:128-34; Etxebarria A et al. PLoS ONE, 2014 Nov;9:e112677). This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000771548	SCV003301335	uncertain significance	Familial hypercholesterolemia	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 859 of the LDLR protein (p.Val859Met). This variant is present in population databases (rs202049029, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 23021490, 25487149). ClinVar contains an entry for this variant (Variation ID: 252360). 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 not expected to disrupt LDLR protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 25386756). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV000771548	SCV002086889	likely benign	Familial hypercholesterolemia	2021-06-04	no assertion criteria provided	clinical testing