Submissions for variant NM_000257.4(MYH7):c.2556G>A (p.Met852Ile)

gnomAD frequency: 0.00001  dbSNP: rs1343088568

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000688110	SCV000815710	likely pathogenic	Hypertrophic cardiomyopathy	2023-05-24	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Met852 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 18403758, 24093860, 27247418). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 567905). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 852 of the MYH7 protein (p.Met852Ile).
Color Diagnostics, LLC DBA Color Health	RCV001176633	SCV001340669	uncertain significance	Cardiomyopathy	2019-02-04	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces methionine with isoleucine at codon 852 of the MYH7 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
AiLife Diagnostics, AiLife Diagnostics	RCV002223906	SCV002502312	uncertain significance	not provided	2021-09-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477535	SCV002785359	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-10-29	criteria provided, single submitter	clinical testing
GeneDx	RCV002223906	SCV004031783	uncertain significance	not provided	2023-02-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published in association with cardiomyopathy to our knowledge; This variant is associated with the following publications: (PMID: 27532257, 29300372, 34542152)