Submissions for variant NM_000527.5(LDLR):c.1171G>A (p.Ala391Thr)

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237576	SCV001960950	benign	Hypercholesterolemia, familial, 1	2021-06-23	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1171G>A (p.Ala391Thr) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1, BS2, BP2 and BP4 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: BA1 - FAF = 0.1752 (17.52%) in African exomes (gnomAD v2.1.1); frequency meets BA1 >0.5% BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in 1894 normolipidemic individuals, as well as in homozygosity in 58 normolipidemic individuals. BP2 - Case-level data present in VCI indicates this variant has been identified to co-occur with Pathogenic LDLR variants in at least 3 index cases with heterozygous FH phenotype. BP4 - REVEL = 0.309; score is below BP4 threshold of <0.50. splicing evaluation is required. Functional data on splicing not available. A) not on limits B) does not create GT C) no nearby GT.
LDLR-LOVD, British Heart Foundation	RCV000237576	SCV000295254	benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
PreventionGenetics, part of Exact Sciences	RCV000241875	SCV000304683	benign	not specified		criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237576	SCV000322933	benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	MAF = 0.10 in normolipidemic controls; MAF = 8,7% in 86 Spanish healthy individuals; 0/200 Brazilian (european ancestry) normolipidemic individuals; 0/100 healthy control individuals; 0/77 healthy control individuals
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000237576	SCV000323101	likely benign	Hypercholesterolemia, familial, 1	2016-08-31	criteria provided, single submitter	research	DLCN criteria >=3.
Illumina Laboratory Services, Illumina	RCV000237576	SCV000410531	benign	Hypercholesterolemia, familial, 1	2018-03-06	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Robarts Research Institute, Western University	RCV000237576	SCV000484696	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	RCV000237576	SCV000503308	benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 201 6 being homozygotes / Software predictions: Benign
GeneDx	RCV000241875	SCV000520997	benign	not specified	2017-01-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237576	SCV000540899	benign	Hypercholesterolemia, familial, 1	2017-03-22	criteria provided, single submitter	clinical testing
Invitae	RCV001082380	SCV000556774	benign	Familial hypercholesterolemia	2024-02-01	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237576	SCV000588559	benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Athena Diagnostics Inc	RCV000241875	SCV000614003	likely benign	not specified	2017-03-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000237576	SCV000689758	benign	Hypercholesterolemia, familial, 1	2017-06-22	criteria provided, single submitter	clinical testing
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000237576	SCV000987023	likely benign	Hypercholesterolemia, familial, 1	2018-07-23	criteria provided, single submitter	clinical testing	Due to the increased occurrence of the mutation (>= 5%), this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000162023	SCV002048889	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326922	SCV002633278	benign	Cardiovascular phenotype	2016-03-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Cohesion Phenomics	RCV001082380	SCV003836762	benign	Familial hypercholesterolemia	2023-02-09	criteria provided, single submitter	clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162023	SCV000189626	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237576	SCV000606341	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000241875	SCV001919018	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000241875	SCV001963329	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001082380	SCV002086410	benign	Familial hypercholesterolemia	2019-10-30	no assertion criteria provided	clinical testing