Submissions for variant NM_000257.4(MYH7):c.3908G>A (p.Arg1303Gln)

dbSNP: rs727505325

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156870	SCV000206591	uncertain significance	not specified	2015-06-22	criteria provided, single submitter	clinical testing	The p.Arg1303Gln variant in MYH7 has been identified by our laboratory in 1 Cauc asian infant with infantile-onset DCM and segregated with disease in 1 affected relative. This variant has been identified in 1/16512 South Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs727505325). Computational prediction tools and conservation analysis suggest t hat the p.Arg1303Gln variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signi ficance of the p.Arg1303Gln variant is uncertain.
Invitae	RCV000461886	SCV000546270	likely pathogenic	Hypertrophic cardiomyopathy	2021-10-23	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.Arg1303 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 24558114), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with dilated cardiomyopathy (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 180067). This variant is present in population databases (rs727505325, ExAC 0.006%). This sequence change replaces arginine with glutamine at codon 1303 of the MYH7 protein (p.Arg1303Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000790939	SCV000930191	uncertain significance	MYH7-Related Disorders	2019-04-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177860	SCV001342142	uncertain significance	Cardiomyopathy	2019-07-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1303 of the MYH7 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	RCV001177860	SCV002042673	uncertain significance	Cardiomyopathy	2020-08-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354384	SCV002620282	uncertain significance	Cardiovascular phenotype	2023-08-24	criteria provided, single submitter	clinical testing	The p.R1303Q variant (also known as c.3908G>A), located in coding exon 27 of the MYH7 gene, results from a G to A substitution at nucleotide position 3908. The arginine at codon 1303 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.