Submissions for variant NM_000257.4(MYH7):c.1987C>A (p.Arg663Ser)

dbSNP: rs397516127

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196247	SCV001366802	likely pathogenic	Congenital myopathy with fiber type disproportion	2019-08-02	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PM5,PP2,PP3,PP4,PP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001349517	SCV001543868	likely pathogenic	Hypertrophic cardiomyopathy	2022-11-29	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg663 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028, 15563892, 15858117, 18383048). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 930519). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239, 30847666). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 663 of the MYH7 protein (p.Arg663Ser).
Ambry Genetics	RCV002418658	SCV002718529	likely pathogenic	Cardiovascular phenotype	2024-04-15	criteria provided, single submitter	clinical testing	The p.R663S variant (also known as c.1987C>A), located in coding exon 16 of the MYH7 gene, results from a C to A substitution at nucleotide position 1987. The arginine at codon 663 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Richard P et al. Circulation, 2003 May;107:2227-32). Other alterations affecting the same amino acid, p.R663C (c.1987C>T) and p.R663H (c.1988G>A), have also been reported in association with HCM and may reflect a mutation hotspot at this position (Gruver EJ et al. Am. J. Cardiol., 1999 Jun;83:13H-18H; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV003106156	SCV003761913	likely pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Identified in patients with HCM in published literature (Richard et al., 2003; van Lint et al., 2019); at least one patient harbored additional cardiogenetic variants; 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: 27532257, 29300372, 30847666, 12707239)