ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3337G>A (p.Ala1113Thr) (rs193922388)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158603 SCV000208538 likely pathogenic not provided 2014-06-04 criteria provided, single submitter clinical testing p.Ala1113Thr (GCA>ACA): c.3337 G>A in exon 27 of the MYH7 gene (NM_000257.2). The A1113T variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. A1113T results in a non-conservative amino acid substitution of a nonpolar Alanine with a polar Threonine at a position that is conserved across species. In silico analysis predicts A1113T is probably damaging to the protein structure/function. Mutations in nearby residues (G1101S, E1116L) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the A1113T 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. 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 HCM panel(s).
Invitae RCV000559337 SCV000623695 uncertain significance Hypertrophic cardiomyopathy 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1113 of the MYH7 protein (p.Ala1113Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 36638). 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). 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.
Integrated Genetics/Laboratory Corporation of America RCV000625702 SCV000696348 uncertain significance not specified 2016-06-02 criteria provided, single submitter clinical testing Variant summary: The c.3337G>A (p.Ala1113Thr) in MYH7 gene is a missense change that involves a conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant is absent from the control population dataset of ExAC. The variant of interest has been reported as Likely Pathogenic by reputable database/clinical laboratory. The variant was identified in a large family where several carriers were unaffected, one HCM individual carried the c.3337G>A in compound heterozygocity with known pathogenic variant c.1988G>A, and one carrier had a SCD at 48. Since most of the carriers of the variant of interest did not have features of HCM and a family history suggests a presence of a hereditary arrhythmia, which could have explain SCD in one carrier, additional clinical, segregation and population data needed to classify this variant with confidence. Taking together, the variant was classified as VUS.

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