Submissions for variant NM_000256.3(MYBPC3):c.1519G>A (p.Gly507Arg)

gnomAD frequency: 0.00177  dbSNP: rs35736435

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035409	SCV000059057	likely benign	not specified	2015-06-12	criteria provided, single submitter	clinical testing	p.Gly507Arg in exon 17 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 0.6% (54/9808) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs35736435).
GeneDx	RCV000587761	SCV000170431	likely benign	not provided	2021-03-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23299917, 12974739, 21310275, 15519027, 17560888, 23217326, 22763267, 23233322, 25637381, 22995991, 24055113, 23820649, 26332594, 30188508)
CSER _CC_NCGL, University of Washington	RCV000148661	SCV000190385	likely benign	Primary familial hypertrophic cardiomyopathy	2014-06-01	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000035409	SCV000203047	benign	not specified	2014-01-07	criteria provided, single submitter	clinical testing
Invitae	RCV001081053	SCV000253164	benign	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490352	SCV000267407	uncertain significance	Hypertrophic cardiomyopathy 4	2016-03-18	criteria provided, single submitter	reference population
PreventionGenetics, part of Exact Sciences	RCV000035409	SCV000303185	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000242061	SCV000319842	likely benign	Cardiovascular phenotype	2018-06-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035409	SCV000696314	likely benign	not specified	2021-11-22	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.1519G>A (p.Gly507Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 249266 control chromosomes, predominantly at a frequency of 0.0054 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy (HCM) phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1519G>A has been reported in the literature in sequencing studies of individuals affected with and/or undergoing multigene panel testing for Hypertrophic Cardiomyopathy (example, Erdmann_2003, Kassem_2013, Lakdawala_2012, Liu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (HCM-MYBPC3 c.2308G>A, p.Asp770Asn; Transthyretin Amylidosis-TTR c.424G>A, p.Val142Ile), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with a predominant consensus leaning towards benign/likely benign (n=9) (VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000035409	SCV000740369	likely benign	not specified	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776189	SCV000911318	likely benign	Cardiomyopathy	2018-04-13	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852652	SCV000995357	benign	Familial amyloid neuropathy	2019-05-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000490352	SCV001138303	benign	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776189	SCV001333616	benign	Cardiomyopathy	2018-12-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587761	SCV004564271	likely benign	not provided	2023-03-28	criteria provided, single submitter	clinical testing