ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2189T>C (p.Ile730Thr) (rs1060501448)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466153 SCV000546256 likely pathogenic Hypertrophic cardiomyopathy 2018-01-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 730 of the MYH7 protein (p.Ile730Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 22429680, Invitae). ClinVar contains an entry for this variant (Variation ID: 407193). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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). A different missense substitution at this codon (p.Ile730Asn) has been determined to be likely pathogenic (PMID: 25935763). This suggests that the isoleucine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be deleterious. 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.

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