Submissions for variant NM_000527.5(LDLR):c.148G>T (p.Ala50Ser)

dbSNP: rs137853960

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV002051650	SCV000190292	uncertain significance	Hypercholesterolemia	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000210234	SCV000266309	likely benign	Hypercholesterolemia, familial, 1	2015-08-31	criteria provided, single submitter	research	MAF =<0.3%
LDLR-LOVD, British Heart Foundation	RCV000210234	SCV000294487	benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000210234	SCV000484686	likely benign	Hypercholesterolemia, familial, 1	2019-08-22	criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000210234	SCV000503105	benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , 2 compound heterozygous / Software predictions: Benign
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455660	SCV000539514	uncertain significance	not specified	2016-03-31	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 5 papers describe as VUS/nonpathogenic; ExAC: 0.1% (67/66532) European; ClinVar: 1 VUS
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000210234	SCV000540896	benign	Hypercholesterolemia, familial, 1	2017-03-16	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000210234	SCV000583635	likely benign	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing	ACMG Guidelines: Pathogenic (ii)
Fundacion Hipercolesterolemia Familiar	RCV000210234	SCV000607422	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000776111	SCV000752432	likely benign	Familial hypercholesterolemia	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776111	SCV000910984	likely benign	Familial hypercholesterolemia	2017-11-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455660	SCV000919594	likely benign	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.148G>T (p.Ala50Ser; also known as p.Ala29Ser) results in a conservative amino acid change located in the first class A repeat domain (IPR002172) of 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 0.00054 in 262944 control chromosomes, predominantly at a frequency of 0.00097 within the Non-Finnish European subpopulation in the gnomAD database. However, in certain European regions the variant was found with a higher allele frequency, e.g. in the Swedish (0.0018), which is higher than estimated maximum expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.0013), suggesting that the variant might be benign. The variant, c.148G>T, has been reported in the literature in individuals affected with hypercholesterolemia, however it was also found in controls and individuals with low LDL cholesterol (Ahmad_2012, Beaudoin_2012, Brusgaard_2006, Chmarra_2010, Do_2015, Ebhardt_1999, Fouchier_2001, Jensen_1994, Junyent_2010, Koeijvoets_2005, Lange_2014, Leren_2004, Tejedor_2010, Geller_2018, Sustar_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. In a family the variant was found to not segregate with disease (Jensen_1994). In addition, co-occurrences with other pathogenic variants have been reported (e.g. LDLR c.12G>A (p.Trp4X); Tejedor_2010 and LDLR c.1033C>T (p.Gln345X) in an internal LCA sample), providing supporting evidence for a benign role. 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: 23064986, 22923420, 16542394, 20145306, 25487149, 24055113, 10090484, 11810272, 30333156, 7820934, 19717150, 15823280, 24507775, 15199436, 10735632, 24956927, 28145427, 20428891, 35913489). 16 other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=12) or VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000210234	SCV001281756	likely benign	Hypercholesterolemia, familial, 1	2018-09-07	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000210234	SCV001429403	uncertain significance	Hypercholesterolemia, familial, 1	2019-02-04	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000058916	SCV001433284	uncertain significance	not provided	2020-02-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000058916	SCV001812513	likely benign	not provided	2020-07-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27044878, 30333156, 7820934, 20506408, 18325082, 16542394, 15576851, 10090484, 26332594, 25487149, 25637381, 22390909, 24055113)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000058916	SCV002046748	likely benign	not provided	2022-07-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390209	SCV002698728	likely benign	Cardiovascular phenotype	2019-01-22	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.
SNPedia	RCV000058916	SCV000090437	not provided	not provided		no assertion provided	not provided
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000210234	SCV000606027	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000210234	SCV000733812	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000455660	SCV001922567	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000455660	SCV001966630	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905026	SCV004725353	likely benign	LDLR-related disorder	2019-06-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).