Submissions for variant NM_000257.4(MYH7):c.1105C>T (p.Arg369Trp)

dbSNP: rs1318155896

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035534	SCV001198863	uncertain significance	Hypertrophic cardiomyopathy	2024-04-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 369 of the MYH7 protein (p.Arg369Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 33906374). ClinVar contains an entry for this variant (Variation ID: 834782). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg369 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20031619, 20530761, 24503780, 24691700; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
All of Us Research Program, National Institutes of Health	RCV004004695	SCV004831641	uncertain significance	Cardiomyopathy	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 369 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. A different variant occurring at the same codon, p.Arg269Gln, is a likely pathogenic mutation (Clinvar variation ID: 42822), indicating that arginine at this position is important for MYH7 protein function. This variant has been identified in 1/251380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789369	SCV005399280	uncertain significance	Dilated cardiomyopathy 1S	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3A. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (N) 0108 - This gene is known to be associated with both recessive and dominant disease, though majority of patients have a single variant (PMID 29300372, PMID 30924982). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID 29300372). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan (exon 12). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif, (head region; PMID 29300372). (P) 0703 – A comparable variant has moderate previous evidence for pathogenicity. The p.(Arg369Gln) (ClinVar, LOVD, PMID:20031619) and p.(Arg369Pro) variants have conflicting evidence of pathogenicity (ClinVar). (P) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign