ClinVar Miner

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

gnomAD frequency: 0.00177  dbSNP: rs35736435
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Total submissions: 16
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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,; 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: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035409 SCV000696314 benign not specified 2024-03-11 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 third 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 0.00058 in 1607036 control chromosomes, predominantly at a frequency of 0.0054 within the African or African-American subpopulation in the gnomAD database (v4.0 dataset), including 1 homozygote. 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 phenotype (0.001), strongly suggesting that the variant is a benign polymorphism. 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 (e.g. Erdmann_2003, Kassem_2013, Lakdawala_2012, Liu_2015). These reports do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. At-least two co-occurrences with other pathogenic variants 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. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated that the variant didn't destabilize protein structure in an in vitro assay (Suay-Corredera_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23217326, 26332594, 23820649, 22995991, 22763267, 24055113, 12974739, 23233322, 22464770, 26090888, 34097875). ClinVar contains an entry for this variant (Variation ID: 42543). Based on the evidence outlined above, the variant was classified as 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
All of Us Research Program, National Institutes of Health RCV001081053 SCV004834608 likely benign Hypertrophic cardiomyopathy 2024-02-05 criteria provided, single submitter clinical testing

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