Submissions for variant NM_000256.3(MYBPC3):c.148A>G (p.Ser50Gly)

gnomAD frequency: 0.00001  dbSNP: rs373164247

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035404	SCV000059052	likely benign	not specified	2015-04-13	criteria provided, single submitter	clinical testing	p.Ser50Gly in exon 2 of MYBPC3: This variant is not expected to have clinical si gnificance because the serine (Ser) residue at position 50 is not conserved in mammals or evolutionarily distant species and >10 mammals carry a glycine (Gly) at this position. In addition, this change was predicted to be benign using a co mputational tool clinically validated by our laboratory. This tool's benign pred iction is estimated to be correct 89% of the time (Jordan 2011). This variant ha s also been identified in 3/43654 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373164247).
GeneDx	RCV000035404	SCV000208386	likely benign	not specified	2017-04-25	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770384	SCV000901825	uncertain significance	Cardiomyopathy	2015-11-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770384	SCV000904643	likely benign	Cardiomyopathy	2018-10-15	criteria provided, single submitter	clinical testing
Invitae	RCV001057933	SCV001222460	uncertain significance	Hypertrophic cardiomyopathy	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 50 of the MYBPC3 protein (p.Ser50Gly). This variant is present in population databases (rs373164247, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42538). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Dept of Medical Biology, Uskudar University	RCV003318337	SCV004022022	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PM2, BP4
All of Us Research Program, National Institutes of Health	RCV001057933	SCV004844983	likely benign	Hypertrophic cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018742	SCV005033669	likely benign	Cardiovascular phenotype	2024-01-18	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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035404	SCV000280213	uncertain significance	not specified	2013-07-15	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser50Gly (c.148 A>G) in the MYBPC3 gene. This variant is novel. It has not been reported in peer reviewed literature, in dbSNP or 1000 Genomes. However it was identified in 1 out of 3500 individuals of Caucasian ancestry in NHLBI’s Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The phenotype of that specific individual is not available to us, however we have been informed that this cohort has been screened to exclude individuals with evidence of Mendelian cardiac disease. It was not observed in 1864 African American individuals in the same dataset (as of December 16, 2011). GeneDx reports that the variant was absent in 100 presumably healthy control individuals of Caucasian descent. This is a non-conservative amino acid change with a neutral, polar Serine replaced with a non-polar Glycine. Serine is not highly conserved at this position with a Glycine in Rhesus monkeys and Threonine in mice and chickens. PolyPhen and SIFT predict that the amino acid change is tolerated. Nearby residues (Thr59Ala) have been reported in association with cardiomyopathy.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701644	SCV001930273	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001701644	SCV001958649	likely benign	not provided		no assertion criteria provided	clinical testing