Submissions for variant NM_000257.4(MYH7):c.2163G>T (p.Arg721Ser)

dbSNP: rs730880734

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158515	SCV000208450	pathogenic	not provided	2012-09-20	criteria provided, single submitter	clinical testing	p.Arg721Ser (AGG>AGT):c.2163 G>T in exon 20 of the MYH7 gene (NM_000257.2). The Arg721Ser mutation in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. However, a mutation affecting this same codon, Arg721Lys, has been reported in association with cardiomyopathy. In addition, multiple mutations in nearby residues (Arg719Gln, Arg719Pro, Arg719Trp, Arg723Cys, Arg723Gly, Arg723His) have been reported in association with cardiomyopathy, further supporting the functional importance of this codon and this region of the protein. Arg721Ser results in a non-conservative amino acid substitution of positively charged Arginine with a neutral, polar Serine at a position that is conserved across species. Furthermore, the NHLBI ESP Exome Variant Server reports Arg721Ser was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, Arg721Ser in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Blueprint Genetics	RCV000158515	SCV000927769	likely pathogenic	not provided	2018-06-29	criteria provided, single submitter	clinical testing
Invitae	RCV002516384	SCV003316898	uncertain significance	Hypertrophic cardiomyopathy	2022-04-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 721 of the MYH7 protein (p.Arg721Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 33673806). ClinVar contains an entry for this variant (Variation ID: 181175). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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). 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.