ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3883G>A (p.Glu1295Lys) (rs730880785)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158623 SCV000208558 likely pathogenic not provided 2014-07-29 criteria provided, single submitter clinical testing p.Glu1295Lys (GAG>AAG): c.3883 G>A in exon 29 of the MYH7 gene (NM_000257.2). A E1295K variant that is likely pathogenic was identified in the MYH7 gene. The E1295K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E1295K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E1295K 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 analysis predicts this variant is probably damaging to the protein structure/function. This substitution occurs at a position that is class conserved across species. Additionally, missense mutations in nearby residues (E1286K, L1297V) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in DCM-CRDM panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000780520 SCV000917847 uncertain significance not specified 2018-10-24 criteria provided, single submitter clinical testing Variant summary: MYH7 c.3883G>A (p.Glu1295Lys) results in a conservative amino acid change located in the Myosin tail of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246272 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3883G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Although nearby missense changes, p.L1297Q, p.L1297V, p.Q1300L, have been reported in affected individuals suggesting that this region could be important for protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

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