Submissions for variant NM_000527.5(LDLR):c.1060+10G>C

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237221	SCV001960954	benign	Hypercholesterolemia, familial, 1	2021-06-23	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1060+10G>C 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 = 0.4446 (44.46%) in European non-Finnish exomes (gnomAD v2.1.1). BS2 - observed in homozygosity in 155 normolipidemic individuals (118 from Color, 22 from INSA, 15 from Western University), as well as in heterozygosity in 376 normolipidemic individuals (297 from Color, 46 INSA, 33 from Western University). BP2 - Variant co-occurs with a Pathogenic LDLR variant (classified by these guidelines) in 6 individuals with a clear heterozygous FH phenotype (LDL-C <8 mmol/L). BP4 - no REVEL, splicing evaluation required. No functional studies variant not on splicing limits, so BP4 is met.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213292	SCV000269221	benign	not specified	2016-03-06	criteria provided, single submitter	clinical testing	c.1060+10G>C in intron 7 of LDLR: This variant is not expected to have clinical significance because it has been identified in 38.5% (46591/121050) of total chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs12710260).
LDLR-LOVD, British Heart Foundation	RCV000237221	SCV000295176	benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
PreventionGenetics, part of Exact Sciences	RCV000213292	SCV000304679	benign	not specified		criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237221	SCV000322928	benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	22 Hmz + 46 Htz / 95 non-FH individuals; MAF = 49,4% in 86 Spanish healthy individuals
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000237221	SCV000323102	likely benign	Hypercholesterolemia, familial, 1	2016-08-31	criteria provided, single submitter	research	MAF =<0.3%
Illumina Laboratory Services, Illumina	RCV000237221	SCV000410530	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.
GeneDx	RCV000213292	SCV000517222	benign	not specified	2016-09-30	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.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237221	SCV000588548	benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Athena Diagnostics	RCV000213292	SCV000614002	benign	not specified	2017-08-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000237221	SCV000689755	benign	Hypercholesterolemia, familial, 1	2017-06-22	criteria provided, single submitter	clinical testing
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000237221	SCV000987005	benign	Hypercholesterolemia, familial, 1	2018-06-08	criteria provided, single submitter	clinical testing	Due to the increased occurrence of the mutation (>= 5%), this variant is classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001275276	SCV001729838	benign	Familial hypercholesterolemia	2025-02-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000237221	SCV001737996	benign	Hypercholesterolemia, familial, 1	2021-06-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812221	SCV002047977	benign	not provided	2024-11-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408921	SCV002717160	benign	Cardiovascular phenotype	2016-03-09	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Cohesion Phenomics	RCV001275276	SCV003836760	benign	Familial hypercholesterolemia	2023-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213292	SCV003929049	benign	not specified	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1060+7_1060+10delinsCCCC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. A constituent SNV, c.1060+10G>C of the variant allele was found at a frequency of 0.39 in 281296 control chromosomes in the gnomAD database (v2.1.1), including 23526 homozygotes. The other constituent SNV of this variant allele, c.1060+7T>C was found at a frequency of 0.9999 in control chromosomes in the gnomAD database (v2.1.1), and therefore, near complete overlap of the c.1060+10G>C occurrences can be assumed. The observed frequency of the c.1060+10G>C variant is approximately 311.25 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1060+7_1060+10delinsCCCC in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
GENinCode PLC	RCV001275276	SCV005045293	benign	Familial hypercholesterolemia		criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001812221	SCV005312089	benign	not provided		criteria provided, single submitter	not provided
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237221	SCV000606306	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001275276	SCV001460267	benign	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000213292	SCV001743196	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000213292	SCV001922064	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000213292	SCV001954536	benign	not specified		no assertion criteria provided	clinical testing