Submissions for variant NM_000527.5(LDLR):c.82G>A (p.Glu28Lys)

gnomAD frequency: 0.00003  dbSNP: rs551747280

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000495866	SCV002817164	uncertain significance	Hypercholesterolemia, familial, 1	2022-10-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.82G>A (p.Glu28Lys) variant is classified as a variant of uncertain significance for Familial Hypercholesterolemia by applying evidence code BP4 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: BP4_Met : REVEL = 0.306. It is below 0.50. splicing evaluation is required. A) not on limits B) does not create AG C) there is a AG nearby The variant does not alter splicing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000495866	SCV000583628	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing	ACMG Guidelines: Pathogenic (i)
Color Diagnostics, LLC DBA Color Health	RCV000775020	SCV000909117	likely benign	Familial hypercholesterolemia	2018-07-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775020	SCV001006786	likely benign	Familial hypercholesterolemia	2024-11-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307522	SCV002600537	likely benign	not specified	2022-10-17	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.82G>A (p.Glu28Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 250844 control chromosomes, predominantly at a frequency of 0.0022 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino 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), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrences of c.82G>A in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating an impact on protein function has been reported in the literature. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Two classified the variant as likely benign, one classified it as VUS, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002431443	SCV002677339	likely benign	Cardiovascular phenotype	2022-11-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
New York Genome Center	RCV000495866	SCV003925258	uncertain significance	Hypercholesterolemia, familial, 1	2022-08-03	criteria provided, single submitter	clinical testing
GeneDx	RCV003322777	SCV004028093	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32719484)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000495866	SCV000606008	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000775020	SCV001463951	uncertain significance	Familial hypercholesterolemia	2020-01-17	no assertion criteria provided	clinical testing