Submissions for variant NM_000257.4(MYH7):c.964T>A (p.Ser322Thr)

dbSNP: rs730880859

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000628973	SCV002041482	uncertain significance	Hypertrophic cardiomyopathy	2021-04-21	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.964T>A (p.Ser322Thr) variant has been reported in at least 3 individuals with HCM (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PM1.
GeneDx	RCV000158773	SCV000208708	likely pathogenic	not provided	2012-09-27	criteria provided, single submitter	clinical testing	p.Ser322Thr (TCC>ACC):c.964 T>A in exon 11 of the MYH7 gene (NM_000257.2). The Ser322Thr variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ser322Thr results in a conservative amino acid substitution of one neutral, polar residue for another at a position that is conserved through mammals. A mutation affecting the same residue (Ser322Phe), as well as mutations in nearby residues (Val320Met, Ala326Pro) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Ser322Thr was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Ser322Thr is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM panel(s).
Invitae	RCV000628973	SCV000749883	uncertain significance	Hypertrophic cardiomyopathy	2017-10-05	criteria provided, single submitter	clinical testing	This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 181330). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with threonine at codon 322 of the MYH7 protein (p.Ser322Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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. 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).