ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3763G>A (p.Ala1255Thr) (rs727503167)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619460 SCV000736168 uncertain significance Cardiovascular phenotype 2017-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Blueprint Genetics, RCV000208079 SCV000264043 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000766380 SCV000208194 uncertain significance not provided 2018-04-30 criteria provided, single submitter clinical testing The A1255T variant of uncertain significance in the MYBPC3 gene has been reported in multiple individuals with HCM (Richard et al., 2003; Kaski et al., 2009; Lopes et al., 2013; Bos et al., 2014; Coppini et al., 2014; Lopes et al., 2015; Mademont-Soler et al., 2017; Walsh et al., 2017). This variant was initially published by Richard et al. (2003) in an adult diagnosed with HCM and, more recently, by Mademont-Soler et al. (2017) in a 40-year-old Spanish male with HCM. A1255T has also been reported in a child with HCM diagnosed prior to 13-years-old (Kaski et al., 2009). Janin et al. (2017) identified A1255T in a 31-year-old female with familial dilated cardiomyopathy (DCM); however, this individual also harbored a truncating FLNC variant. This variant has been reported in several probands referred to GeneDx for HCM genetic testing; however, detailed clinical information or informative segregation data are unavailable. The A1255T 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. Moreover, in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, A1255T was observed in 11/34,414 (0.03%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). A missense variant in the same residue (A1255T) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), however the pathogenicity of this variant has not been definitively determined. The A1255T variant lacks informative segregation data and functional evidence, which would further clarify pathogenicity. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina RCV000778327 SCV000914514 pathogenic Familial hypertrophic cardiomyopathy 4 2018-08-16 criteria provided, single submitter clinical testing The MYBPC3 c.3763G>A (p.Ala1255Thr) missense variant has been reported in at least five studies in which it was identified in a heterozygous state in nine individuals with hypertrophic cardiomyopathy, although co-segregation with disease in a family has not been clearly reported (Richard et al. 2003; Kaski et al. 2009; Lopes et al. 2013; Coppini et al. 2014; Walsh et al. 2017). The p.Ala1255Thr variant was absent from 200 chromosomes from healthy adult controls (Richard et al. 2003) and is reported at a frequency of 0.000320 in the Latino population of the Genome Aggregation Database. The p.Ala1255 residue is highly conserved and located in the functionally important C10 protein domain. Based on the collective evidence, the p.Ala1255Thr variant is classified as pathogenic for hypertrophic cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000628880 SCV000749788 uncertain significance Hypertrophic cardiomyopathy 2017-12-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1255 of the MYBPC3 protein (p.Ala1255Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs727503167, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 23396983,27532257, 20031618, 25524337). ClinVar contains an entry for this variant (Variation ID: 164023). 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 and their clinical significance is uncertain. Experimental studies have shown that this missense change disrupts normal splicing (PMID: 28679633). 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 RCV000151059 SCV000198796 uncertain significance not specified 2016-02-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala1255Thr variant in MYBPC3 has been reported in 5 individuals with hypertrophic cardiomyopathy, including one individual who also carried a heterozygous, likely pathogenic variant in another gene (Richard 2003, Lopes 2013, Coppini 2014, LMM data). The p.Ala1255Thr variant has been identified in 0.01% (8/66,178) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ala1255Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1255Thr variant is uncertain.

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