Submissions for variant NM_000257.4(MYH7):c.5588G>A (p.Arg1863Gln)

gnomAD frequency: 0.00001  dbSNP: rs45520836

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000758051	SCV000564460	uncertain significance	Primary dilated cardiomyopathy	2021-03-22	reviewed by expert panel	curation	The c.5588G>A (p.Arg1863Gln) variant in MYH7 has been identified in 1 individual with familial DCM (Hershberger 2008 PMID:19412328) and 7 individuals with DCM from clinical testing laboratories (PS4_Moderate; PMID:19412328; Partners LMM ClinVar SCV000059623.5; Invitae ClinVar SCV000818269.1, pers. comm.; Ambry pers. comm.; CHEO ClinVar SCV000901909.1, pers. comm.; GeneDx ClinVar SCV000208646.4, pers. comm.). This variant was also identified in 0.00027% (FAF 95% CI; 2/129158) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2; PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035971	SCV000059623	uncertain significance	not specified	2015-06-24	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1863Gl n variant in MYH7 has been reported in 1 individual with DCM (Hershberger 2008). This variant has also been identified by our laboratory in 1 male infant with D CM and Barth Syndrome who also carried a likely pathogenic variant in the TAZ ge ne. Both this variant and the likely pathogenic TAZ variant were also identified in 1 affected relative from the same family. This variant has been identified 1 /66706 European chromosomes by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs45520836), but this likely represents the sample reported by Hershberger 2008 as this study was part of the NHLBI sequencing proj ect and is now included in ExAC. Arginine (Arg) at position 1863 is highly conse rved in mammals and across evolutionarily distant species and the change to glut amine (Gln) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspic ion for a pathogenic role, the clinical significance of the p.Arg1863Gln variant is uncertain.
GeneDx	RCV000766472	SCV000208646	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	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: 22337857, 23403236, 23299917, 27576561, 29300372, 32439065, 19412328)
Invitae	RCV000690579	SCV000818269	pathogenic	Hypertrophic cardiomyopathy	2023-10-13	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 1863 of the MYH7 protein (p.Arg1863Gln). This variant is present in population databases (rs45520836, gnomAD 0.003%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 19412328; Invitae). ClinVar contains an entry for this variant (Variation ID: 43076). 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. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770466	SCV000901909	uncertain significance	Cardiomyopathy	2016-11-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770466	SCV001355516	uncertain significance	Cardiomyopathy	2023-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1863 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 dilated cardiomyopathy (PMID: 19412328, 29300372, 30847666). This variant has been identified in 3/282516 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.
Ambry Genetics	RCV002345283	SCV002650965	uncertain significance	Cardiovascular phenotype	2021-01-29	criteria provided, single submitter	clinical testing	The p.R1863Q variant (also known as c.5588G>A), located in coding exon 36 of the MYH7 gene, results from a G to A substitution at nucleotide position 5588. The arginine at codon 1863 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in an individual reported to have familial dilated cardiomyopathy, and has also been seen in an exome cohort, but cardiovascular history was not provided (Hershberger RE et al. Clin Transl Sci. 2008;1(1):21-6; Andreasen C et al. Eur J Hum Genet. 2013;21(9):918-28). This variant was also detected in one individual in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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.
Fulgent Genetics, Fulgent Genetics	RCV002490491	SCV002782348	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	2021-09-15	criteria provided, single submitter	clinical testing