Submissions for variant NM_000257.4(MYH7):c.3830G>A (p.Arg1277Gln)

gnomAD frequency: 0.00001  dbSNP: rs397516195

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035869	SCV000059520	uncertain significance	not specified	2016-09-01	criteria provided, single submitter	clinical testing	The p.Arg1277Gln variant in MYH7 has been identified in 2 individuals with HCM a nd 1 individual with left ventricular hypertrophy, though one of these individua ls also carried an additional likely disease causing variant in another gene (Zo u 2013, LMM data). It has also been identified in 2/66738 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516195). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Arg1277Gln variant is uncertain.
GeneDx	RCV000035869	SCV000490655	uncertain significance	not specified	2016-10-14	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH7 gene. The R1277Q variant has been reported in two Chinese patients with HCM; however, one patient also harbored a loss of function variant in the MYBPC3 gene (Zou et al., 2013). Additionally, this variant has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000059520.4; Landrum et al., 2016). The R1277Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1277Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000475071	SCV000546269	uncertain significance	Hypertrophic cardiomyopathy	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1277 of the MYH7 protein (p.Arg1277Gln). This variant is present in population databases (rs397516195, gnomAD 0.009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23283745, 27532257). ClinVar contains an entry for this variant (Variation ID: 42976). 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.
Fulgent Genetics, Fulgent Genetics	RCV000765160	SCV000896389	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-07-28	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000788815	SCV000928071	uncertain significance	not provided	2018-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001189926	SCV001357320	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1277 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 23283745, 27532257, 31104103). Some of these individuals also carried pathogenic variants in the MYBPC3 and MYL2 genes that could explain the observed phenotype (PMID: 23283745, 31104103). This variant has also been reported in a family affected with myosin storage myopathy (DOI:10.21203/rs.2.19928/v1). This variant has been identified in 12/251468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001189926	SCV002042671	uncertain significance	Cardiomyopathy	2020-09-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000788815	SCV003815406	uncertain significance	not provided	2020-12-29	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318340	SCV004022059	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PM2, PP2
PreventionGenetics, part of Exact Sciences	RCV003407401	SCV004109238	uncertain significance	MYH7-related condition	2023-03-28	criteria provided, single submitter	clinical testing	The MYH7 c.3830G>A variant is predicted to result in the amino acid substitution p.Arg1277Gln. This variant has been reported in individuals with hypertrophic cardiomyopathy (Zou et al. 2013. PubMed ID: 23283745; Table S1B, Walsh et al. 2016. PubMed ID: 27532257). However, this variant has also reported in control populations (Table S6, Park et al. 2022. PubMed ID: 34542152) and is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23888715-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.