Submissions for variant NM_000257.4(MYH7):c.3645G>C (p.Gln1215His)

dbSNP: rs863225096

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201442	SCV000256131	likely pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing
GeneDx	RCV000523764	SCV000617293	uncertain significance	not provided	2017-07-31	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH7 gene. The Q1215H variant has been reported in at least two individuals in association with HCM, including one individual who harbored an additional variant in a different gene (Marsiglia et al., 2013; Homburger et al., 2016; Alejandra Restrepo-Cordoba et al., 2017); however, no segregation studies were reported. It is also reported as a likely pathogenic variant in ClinVar by a different clinical laboratory (SCV000256131.1; Landrum et al., 2016), although additional evidence is not available. The Q1215H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, Q1215H is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been observed in a significant number of affected individuals and it lacks both segregation and functional studies which would further clarify its pathogenicity.
Invitae	RCV002517305	SCV003442254	uncertain significance	Hypertrophic cardiomyopathy	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1215 of the MYH7 protein (p.Gln1215His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24093860, 27247418). ClinVar contains an entry for this variant (Variation ID: 217463). 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%. 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.