Submissions for variant NM_000257.4(MYH7):c.2087A>G (p.Asn696Ser)

dbSNP: rs730880732

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158507	SCV000208442	likely pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Jskelinen et al., 1998; Millat et al., 2010; Teirlinck et al., 2012; Ross et al., 2017; Mattivi et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23140321, 9822100, 24888384, 27532257, 29300372, 28615295, 28265379, 31006259, 32894683, 20800588)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000803464	SCV000692496	likely pathogenic	Hypertrophic cardiomyopathy	2018-08-24	criteria provided, single submitter	research	The MYH7 Asn696Ser variant has been reported previously in 6 HCM probands (GeneDx, Pers. Comm.; Jaaskelainen P, et al., 2014; Teirlinck CH, et al., 2012; Millat G, et al., 2010; Jaaskelainen P, et al., 1998). One of the probands was also reported to carry MYH7 Met982Thr (Millat G, et al., 2010), however this variant is found at high frequency in population databases (MAF=0.0009; http://exac.broadinstitute.org/), which is highly suggestive of a benign polymorphism. The MYH7 Asn696Ser is very rare, being absent from the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We identified this variant in one HCM proband (Ingles J et al., 2017), who was diagnosed at 12 years after suffering a resuscitated cardiac arrest. The proband has no family history of HCM or sudden cardiac death, and neither of the parents were found to harbour this variant, therefore this variant has arisen de novo. Computational tools SIFT, PolyPhen-HCM, MutationTaster predict this variant to have a deleterious effect, however PolyPhen2 predicts this variant to be "benign". In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. In summary, based on the adapted ACMG guidelines (Kelly MA, et al., 2018) the variant is located in a known functional domain of MYH7 (PM1), is rare in the general population (PM2), has been identified in a de novo case (PM6) and has been reported in a total of 7 HCM probands (PS4_moderate), therefore we classify MYH7 Asn696Ser as 'likely pathogenic'.
Invitae	RCV000803464	SCV000943336	pathogenic	Hypertrophic cardiomyopathy	2023-04-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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). 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: 181173). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9822100, 28615295; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 696 of the MYH7 protein (p.Asn696Ser).