ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.710A>C (p.Tyr237Ser) (rs397516070)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208413 SCV000264022 pathogenic Primary familial hypertrophic cardiomyopathy 2015-10-15 criteria provided, single submitter clinical testing
GeneDx RCV000254667 SCV000208242 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing The Y237S pathogenic variant in the MYBPC3 gene has been reported in association with HCM (Mörner et al., 2003; Berge et al., 2014; Walsh et al., 2017). This variant has also been observed in multiple other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. In addition, the Y237S variant was found to segregate with disease in several affected relatives from two unrelated families tested at GeneDx and another clinical laboratory (Laboratory for Molecular Medicine pers comm). The Y237S variant is not observed in large population cohorts (Lek et al., 2016). Y237S is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, different missense variants affecting the same residue (Y237C, Y237H) have also been reported in association with HCM (Garcia-Castro et al., 2009; Waldmüller et al., 2008), further supporting the functional importance of this residue.
Invitae RCV000525151 SCV000623618 likely pathogenic Hypertrophic cardiomyopathy 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 237 of the MYBPC3 protein (p.Tyr237Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 12818575, 24111713). ClinVar contains an entry for this variant (Variation ID: 42787). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000525151 SCV000059314 pathogenic Hypertrophic cardiomyopathy 2018-04-30 criteria provided, single submitter clinical testing The p.Tyr237Ser variant in MYBPC3 has been identified in at least 10 individuals with HCM and segregated with disease in 10 affected relatives, including 2 obli gate carriers, from 2 families (Morner 2003, Walsh 2017, GeneDx pers comm., LMM data). It has not been identified in large population studies. Computational pre diction tools and protein structural modeling suggest that the p.Tyr237Ser varia nt impacts the protein (Govada 2008). Additionally, other variants at this posit ion (p.Tyr237His and p.Tyr237Cys) have been reported in individuals with HCM, su ggesting that variation at this position is not tolerated (Waldmuller 2008, Garc ia-Castro 2009). In summary, the p.Tyr237Ser variant meets criteria to be classi fied as pathogenic for HCM in an autosomal dominant manner based on case observa tions, segregation studies, and absence from controls. ACMG/AMP criteria applied : PP1_VeryStrong, PM2, PS4_Moderate, PP3.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158307 SCV000280278 uncertain significance not specified 2012-01-12 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.Tyr237Ser (c.710A>C) in MYBPC3. Based on the data reviewed below, we consider this variant to be a variant of uncertain significance, probably disease causing. This variant has been reported in one familial HCM case in Northern Sweden. The proband with this variant was diagnosed with HCM at 37. He had 11 first degree relatives, seven of whom were evaluated. Out of the seven, one relative also had HCM. Co-segregation analysis was not performed (Morner et al., 2003). This is a conservative amino acid change with a neutral polar Tyrosine replaced with a neutral polar Serine. Tyrosine at position 237 is highly conserved in MYBPC3 across species. In silico analysis (PolyPhen 2) predicts the variant to be probably damaging. Other variants at this same codon have been reported in association with HCM: p.Tyr237His (Waldmuller et al., 2008); p.Tyr237Cys (Garcia-Castro et al., 2009); p.Tyr237X (Ehlermann et al., 2008), as have variants at nearby codons: p. Asp228Asn (Andersen et al., 2001; Andersen et al., 2004); p.Ser236Gly (Daehmlow et al., 2002; Fokstuen et al., 2008; Girolami et al., 2006; Jaaskerlainen et al., 2002; Morita et al., 2006, and Wang et al., 2009) and p.Glu240Asp (Girolami et al., 2006). In total, the variant has not been observed in ~7,000 control individuals from published studies and publicly available general population samples. The variant has not been seen in Familion's control population of 400 presumably health individuals. Morner et al (2003) reported the absence of the variant in at least 100 presumably healthy control individuals. The variant is not reported in dbSNP or 1000 genomes (as of January 29, 2014) The variant is not listed in NHLBI Exome Sequencing Project (as of January 29, 2014), which includes variant calls on ~6,500 Caucasian and African American individuals.

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