Submissions for variant NM_000527.5(LDLR):c.148G>T (p.Ala50Ser) (rs137853960)

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000148578	SCV000190292	uncertain significance	Hypercholesterolaemia	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	Familial hypercholesterolemia 1	2015-08-31	criteria provided, single submitter	research	MAF =<0.3%
LDLR-LOVD, British Heart Foundation	RCV000210234	SCV000294487	benign	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute,Western University	RCV000210234	SCV000484686	likely benign	Familial hypercholesterolemia 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	Familial hypercholesterolemia 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,Partners HealthCare 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	Familial hypercholesterolemia 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	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing	ACMG Guidelines: Pathogenic (ii)
Fundacion Hipercolesterolemia Familiar	RCV000210234	SCV000607422	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000776111	SCV000752432	likely benign	Familial hypercholesterolemia	2019-12-31	criteria provided, single submitter	clinical testing
Color	RCV000776111	SCV000910984	likely benign	Familial hypercholesterolemia	2017-11-23	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000455660	SCV000919594	likely benign	not specified	2020-09-16	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 Low-density lipoprotein (LDL) receptor class A repeat region 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 0.00051 in 294358 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00051 vs 0.0013), allowing no conclusion about variant significance. The variant, c.148G>T, has been reported in the literature in individuals affected with Familial Hypercholesterolemia but also 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). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. In one family, the variant was found to not segregate with disease (Jensen_1994). Co-occurrences with other pathogenic variants have been reported (LDLR c.12G>A, p.Trp4X; LDLR c.1033C>T, p.Gln345X), providing supporting evidence for a benign role (Tejedor_2010, internal database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x), likely benign (6x) and benign (3x). Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Clinical Services Laboratory,Illumina	RCV000210234	SCV001281756	likely benign	Familial hypercholesterolemia 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	Familial hypercholesterolemia 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
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	Familial hypercholesterolemia 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen	RCV000210234	SCV000733812	benign	Familial hypercholesterolemia 1		no assertion criteria provided	clinical testing