ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1246G>A (p.Gly416Ser) (rs371513491)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035380 SCV000059028 uncertain significance not specified 2016-04-14 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000035380 SCV000208005 uncertain significance not specified 2017-05-31 criteria provided, single submitter clinical testing p.Gly416Ser (GGT>AGT): c.1246 G>A in exon 15 of the MYBPC3 gene (NM_000256.3) The G416S variant in the MYBPC3 gene has been reported in association with cardiomyopathy (Song et al., 2005; Pugh et al., 2014; Lopes et al., 2015). However, this variant has also been published as a benign variant (Van Driest et al., 2004; Girolami et al., 2006). Additionally, the G416S variant has been classified by other clinical laboratories in ClinVar as a variant of uncertain significance (SCV000284108.1, Landrum et al., 2016) and as a likely benign variant (SCV000059028.4). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The NHLBI Exome Sequencing Project reports G416S was observed in approximately 3/4,228 alleles from individuals of African American backgrounds. This substitution occurs at a position that is not conserved across species and where Serine is the wild type in two species. Nevertheless, the G416S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000226889 SCV000284208 uncertain significance Hypertrophic cardiomyopathy 2016-02-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 416 of the MYBPC3 protein (p.Gly416Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs371513491, ExAC 0.04%). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 15563892). However, it has also been reported in 2/100 unaffected individuals (PMID: 15519027). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not. ClinVar contains an entry for this variant (Variation ID: 42515). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function that has been reported in affected patients as well as in healthy individuals and has not been demonstrated to segregate with disease. In the absence of confirmed segregation evidence, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000621944 SCV000736573 uncertain significance Cardiovascular phenotype 2016-05-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625310 SCV000744855 uncertain significance Familial hypertrophic cardiomyopathy 4 2017-05-31 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148682 SCV000190407 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

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