Submissions for variant NM_000257.4(MYH7):c.3422G>A (p.Arg1141Gln)

dbSNP: rs1407919500

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000774488	SCV000908191	uncertain significance	Cardiomyopathy	2023-10-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1141 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 not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 1/234818 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.
GeneDx	RCV001575007	SCV001801916	uncertain significance	not provided	2020-06-24	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 629776; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Invitae	RCV001856089	SCV002120997	uncertain significance	Hypertrophic cardiomyopathy	2023-07-19	criteria provided, single submitter	clinical testing	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. 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: 629776). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1141 of the MYH7 protein (p.Arg1141Gln).
PreventionGenetics, part of Exact Sciences	RCV003396343	SCV004119780	uncertain significance	MYH7-related condition	2022-11-10	criteria provided, single submitter	clinical testing	The MYH7 c.3422G>A variant is predicted to result in the amino acid substitution p.Arg1141Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00095% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23889358-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.