ClinVar Miner

Submissions for variant NM_000257.3(MYH7):c.341T>C (p.Ile114Thr) (rs730880833)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158728 SCV000208663 likely pathogenic not provided 2013-01-25 criteria provided, single submitter clinical testing p.Ile114Thr (ATC>ACC): c.341 T>C in exon 4 of the MYH7 gene (NM_000257.2). The Ile114Thr variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ile114Thr results in a non-conservative amino acid substitution of a non-polar Isoleucine with a neutral, polar Threonine at a position that is conserved across species. In silico analysis predicts Ile114Thr is probably damaging to the protein structure/function. Mutations in nearby residues (Tyr115His, Thr124Ile) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the Ile114Thr variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Ile114Thr is a good candidate for a disease-causing mutation. The variant is found in HCM panel(s).
Invitae RCV000543876 SCV000623697 uncertain significance Hypertrophic cardiomyopathy 2017-03-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 114 of the MYH7 protein (p.Ile114Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs730880833, ExAC 0.001%) but has not been reported in the literature in individuals with a MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 181300). 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, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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