ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.707T>C (p.Val236Ala) (rs397516262)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035992 SCV000059644 uncertain significance not specified 2011-05-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Val236Ala v ariant has not been previously reported in the literature, but has been identifi ed in one out of >1800 Caucasian probands (3600 chromosomes) tested by our labor atory (this individual?s father). This low frequency supports a pathogenic role . In addition, valine (Val) at amino acid position is highly conserved across m ammals, chicken, and frog (though zebrafish carries an isoleucine), which increa ses the chance that a change many not be tolerated. Furthermore, the vast majori ty of missense variants in MYH7 are pathogenic (LMM unpublished data), which inc reases the likelihood that this variant is disease causing. However, this varian t was predicted to be benign using a novel computational tool, which was validat ed by our laboratory using a set of cardiomyopathy variants with well-establishe d clinical significance. This tool's benign interpretation is estimated to be co rrect 89% of the time, which suggests but does not prove that this variant is be nign (Jordan 2011). Additionally, results from other computational prediction to ols are mixed. AlignGVGD and Polyphen2 predict this change to be benign, while S IFT predicts this change to be pathogenic. However, these tools have not been va lidated sufficiently to determine pathogenicity. Collectively, this data suggest s the Val236Ala may play a role in disease, but additional data is required to f ully assess this variant. Therefore, this clinical significance of this variant cannot be determined at this time.
GeneDx RCV000767174 SCV000279743 uncertain significance not provided 2016-01-04 criteria provided, single submitter clinical testing The V236A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been reported as a variant of uncertain significance in the ClinVar database by an outside laboratory (Landrum et al., 2014). The V236A 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. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, the V236A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Blueprint Genetics RCV000767174 SCV000927894 likely pathogenic not provided 2018-08-30 criteria provided, single submitter clinical testing

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