ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.649A>G (p.Ser217Gly) (rs138753870)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172559 SCV000051402 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035656 SCV000059307 benign not specified 2015-05-20 criteria provided, single submitter clinical testing p.Ser217Gly in exon 5 of MYBPC3: This variant is not expected to have clinical s ignificance because it has been identified in 1.2% (177/14558) of South Asian ch romosomes, including 4 homozygotes, by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org; dbSNP rs138753870).
GeneDx RCV000035656 SCV000208236 benign not specified 2017-12-11 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.
Invitae RCV001082031 SCV000261419 benign Hypertrophic cardiomyopathy 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618826 SCV000736843 benign Cardiovascular phenotype 2016-05-17 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000035656 SCV000748014 likely benign not specified 2017-02-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771156 SCV000903002 benign Cardiomyopathy 2018-03-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001105224 SCV001262155 benign Left ventricular noncompaction 10 2018-06-04 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001105225 SCV001262156 uncertain significance Familial hypertrophic cardiomyopathy 4 2018-06-04 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035656 SCV001363316 benign not specified 2019-11-26 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.649A>G (p.Ser217Gly) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 240264 control chromosomes, predominantly at a frequency of 0.011 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.649A>G has been reported in the literature in individuals affected with affected with hypertrophic- or dilated cardiomyopathy, however without strong evidence for causality (e.g. Roberts_2009, Millat_2010, Ogorodnikova_2011, Mestroni_2010, Lakdawala_2012, Merlo_2013, Pugh_2014). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Additionally, Lakdawala_2012 reported that this variant did not segregate with the disease in one family. Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.2827C>T (p.Arg943X) in an internal sample; MYH7 c.1357C>T, (p.Arg453Cys) in Roberts_2009), providing supporting evidence for a benign role. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (5x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000172559 SCV000280276 likely benign not provided 2016-03-01 no assertion criteria provided provider interpretation reclassified based on 2015 re-review. Data from that re-review is summarized in DOI: 10.1161/CIRCGENETICS.116.001700.

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