Submissions for variant NM_000257.4(MYH7):c.5459G>A (p.Arg1820Gln)

gnomAD frequency: 0.00004  dbSNP: rs371855540

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766386	SCV000566975	uncertain significance	not provided	2018-09-12	criteria provided, single submitter	clinical testing	The R1820Q variant of uncertain significance in the MYH7 gene has been previously reported in two sisters with distal myopathy, one of whom developed supraventricular tachycardia and HCM at the age of 64 years, however, it was absent from a third sibling with isolated distal myopathy (Brand et al., 2016). Brand et al. (2016) reported that all three siblings in this family also harbored a pathogenic missense variant in the TIA1 gene, which is associated with Welander distal myopathy, and this family had a paternal family history of cardiac disease but further segregation studies of the R1820Q variant were not reported. The R1820Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, R1820Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this substitution occurs at a position that is conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, although a missense variant at the same residue in the MYH7 gene (R1820W) has been reported in the Human Gene Mutation Database in association with myopathy (Stenson et al., 2014), the clinical significance of this variant also remains to be definitively determined.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000487258	SCV000711403	uncertain significance	not specified	2019-07-26	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1820Gln variant in MYH7 has been reported in 1 individual with both hypertrophic cardiomyopathy and distal myopathy as well as in one sibling with only myopathy; however, both individuals as well as a third affected sibling had an additional pathogenic variant sufficient to cause distal myopathy, but which has not been previously associated with cardiomyopathy (Brand 2016). It has also been identified in 1 individual with HCM (LMM data) and has been identified in 5/251346 chromosomes by gnomAD (https://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID #419278). Computational prediction tools and conservation analysis suggest that the p.Arg1820Gln variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria Applied: PM2, PS4_Supporting, PP3.
Color Diagnostics, LLC DBA Color Health	RCV001176567	SCV001340587	uncertain significance	Cardiomyopathy	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1820 of the MYH7 protein. Computational prediction suggests that this variant may have 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 an individual affected with hypertrophic cardiomyopathy (PMID: 27282841). This variant has been identified in 5/251346 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.
Invitae	RCV001232041	SCV001404584	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-11	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 1820 of the MYH7 protein (p.Arg1820Gln). This variant is present in population databases (rs371855540, gnomAD 0.006%). This missense change has been observed in individual(s) with distal myopathy (PMID: 27282841). This variant has been reported in individual(s) with autosomal dominant hypertrophic cardiomyopathy (Invitae); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 419278). 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%. This variant disrupts the p.Arg1820 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25666907). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Fulgent Genetics, Fulgent Genetics	RCV002481505	SCV002788812	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	2021-09-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001176567	SCV004239484	uncertain significance	Cardiomyopathy	2023-06-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001176567	SCV004831071	uncertain significance	Cardiomyopathy	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1820 of the MYH7 protein. Computational prediction suggests that this variant may have 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 an individual affected with hypertrophic cardiomyopathy (PMID: 27282841). This variant has been identified in 5/251346 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	RCV004023121	SCV005033999	uncertain significance	Cardiovascular phenotype	2024-03-11	criteria provided, single submitter	clinical testing	The p.R1820Q variant (also known as c.5459G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5459. The arginine at codon 1820 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in two of three siblings in a family, all of whom also carried the TIA1 p.E384K alteration. Phenotypes of the two siblings with both alterations included progressive asymmetric distal limb weakness, mild distal myopathy, supraventricular tachycardia and hypertrophic cardiomyopathy. The third sibling who only carried the TIA1 alteration had isolated distal myopathy (Brand P et al. Neuromuscul. Disord., 2016 08;26:511-5). This variant has also been reported in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) and co-occurring DSG2 variants, as well as in an exome cohort with limited clinical details (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Lin Y et al. J Electrocardiol Jun;51:837-843). This alteration also been reported in association with transposition of the great arteries (Blue GM et al. Am Heart J, 2022 Feb;244:1-13). 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.