ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3797G>A (p.Cys1266Tyr) (rs397516041)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766384 SCV000208205 uncertain significance not provided 2018-09-13 criteria provided, single submitter clinical testing The C1266Y variant of uncertain significance in the MYBPC3 gene has previously been reported in association with HCM (Page et al., 2012; Walsh et al., 2017). This variant has also been observed in other unrelated individuals referred to GeneDx for HCM genetic testing. Internal segregation data are uninformative due to lack of clinical information received. The C1266Y variant is not observed in large population cohorts (Lek et al., 2016). C1266Y 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. In addition, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Although different missense variants at the same residue (C1266R, C1266W) have been reported in the Human Gene Mutation Database and/or at GeneDx in association with HCM (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Additional evidence is needed to clarify pathogenicity of the C1266Y variant, including observation in a significant number of affected individuals, informative segregation data, and functional evidence.
Integrated Genetics/Laboratory Corporation of America RCV000780507 SCV000917819 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-12-18 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.3797G>A (p.Cys1266Tyr) variant involves the alteration of a conserved nucleotide located in the Immunoglobulin-like fold (InterPro). 4/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 276518 control chromosomes and has been reported in two HCM patients from the literature, one of which was a large clinical study (Page_2012, Walsh_2017), one patient being tested for HCM from a reputable clinical lab (GeneDx), and in two affected individuals within a family referred for HCM testing at our laboratory. In addition, two clinical diagnostic laboratories cite the variant with conflicting classifications (VUS, likely pathogenic). Taken together, this variant is classified as likely pathogenic.
Invitae RCV000696277 SCV000824829 uncertain significance Hypertrophic cardiomyopathy 2018-05-31 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1266 of the MYBPC3 protein (p.Cys1266Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 27532257). ClinVar contains an entry for this variant (Variation ID: 42743). A computational algorithm designed to assess the pathogenicity of variants in MYBPC3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000505727 SCV000059269 uncertain significance not specified 2017-03-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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