ClinVar Miner

Submissions for variant NM_000257.3(MYH7):c.4954G>T (p.Asp1652Tyr) (rs397516233)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584779 SCV000692493 uncertain significance Familial hypertrophic cardiomyopathy 1 2017-03-09 criteria provided, single submitter research This MYH7 Asp1652Tyr variant has been described in two Italian HCM patients (Frisso G, et al., 2009; Roncarati R, et al., 2011). Segregation analysis provided by Frisso G et al. (2009) identified two family members who also carry this variant. Both members however, did not have typical HCM characteristics but rather a dilated (proband's sister) and restrictive (proband's father) cardiomyopathy phenotype. We have identified this MYH7 Asp1652Tyr variant in an isolated HCM patient of North West European descent. Clinical screening of the family revealed no family history of HCM and/or sudden cardiac death. We note that additional uncertain variants have been identified in the proband which may contribute to the disease phenotype (MYL2 Ala13Thr; DSG2 Asp535Glu). The MYH7 Asp1652Tyr variant is absent in 1000 genomes project (, and has a frequency of 0.00002475 in the Exome Aggregation Consortium dataset ( Aspartic acid at position 1652 is highly conserved across distantly related species, and computational tools predict the Asp1652Tyr to be "deleterious" (SIFT) and "disease-causing" (MutationTaster). Additionally, Polyphen_HCM (Jordan DM, et al., 2011) predicts that this MYH7 Asp1652Tyr variant is causative of the disease. Based on this information, we classify MYH7 Asp1652Tyr as a variant of "uncertain significance".
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769441 SCV000900834 uncertain significance Cardiomyopathy 2015-07-31 criteria provided, single submitter clinical testing
GeneDx RCV000766465 SCV000208613 uncertain significance not provided 2018-08-06 criteria provided, single submitter clinical testing The c.4954 G>T (D1652Y) variant in the MYH7 gene has been reported previously in three individuals from one family, each with a different cardiomyopathy presentation (DCM, HCM and restrictive cardiomyopathy) (Frisso et al., 2009). In addition, c.4954 G>T was reported in one individual with early onset HCM and a family history of sudden death, however only two genes (MYH7 and MYBPC3) were analyzed in this family (Roncarati et al., 2011). The c.4954 G>T variant is observed in 5/33580 alleles (0.015%) from individuals of Latino background in large population cohorts (Lek et al., 2016). In-silico splice models predict that c.4954 G>T may damage natural splicing acceptor site for intron 34. However, in the absence of RNA/functional studies, the actual effect of c.4954 G>T in this individual is unknown. If c.4954 G>T does not alter splicing, it will result in the D1652Y missense change. The D1652Y 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the available evidence, it is unclear if c.4954 G>T (D1652Y) is pathogenic or benign. Therefore, we interpret D1652Y as a variant of uncertain significance.
Invitae RCV000694818 SCV000823280 likely pathogenic Hypertrophic cardiomyopathy 2018-03-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 1652 of the MYH7 protein (p.Asp1652Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs397516233, ExAC 0.005%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 19659763, 21302287, 27247418, 27532257, 28790153). ClinVar contains an entry for this variant (Variation ID: 43047). A computational algorithm designed to assess the pathogenicity of variants in MYH7 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000035941 SCV000059592 uncertain significance not specified 2014-01-02 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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