Submissions for variant NM_002471.4(MYH6):c.1328G>A (p.Arg443His)

gnomAD frequency: 0.00006  dbSNP: rs202096001

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172032	SCV000050998	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Ambry Genetics	RCV002381559	SCV002693022	uncertain significance	Cardiovascular phenotype	2022-10-26	criteria provided, single submitter	clinical testing	The p.R443H variant (also known as c.1328G>A), located in coding exon 11 of the MYH6 gene, results from a G to A substitution at nucleotide position 1328. The arginine at codon 443 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This alteration has also been reported in a drug-induced arrhythmia/sudden unexplained death cohort (Martinez-Matilla M et al. Forensic Sci Int Genet, 2019 09;42:203-212). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470787	SCV002768901	uncertain significance	Hypertrophic cardiomyopathy 14	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as a VUS-3C Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v.2.1.1) <0.001 for a dominant condition (26 heterozygotes, 0 homozygotes) with the S. Asian frequency of 0.00059 (18 heterozygotes). (SP) 0309 - An alternative amino acid change, p.(Arg443Cys) at the same position has been observed in gnomAD (v2.1.1) (30 heterozygotes, 0 homozygotes) with the E. Asian frequency of 0.001 (21 heterozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools. Very high conservation but minor amino acid change. (SP) 0600 - Variant is located in the annotated myosin head (motor domain) (RCSB PDB, UniProt, NCBI_Conserved domains, DECIPHER). (I) 0708 - Other missense variants at the same position, and all causing major amino acid changes, have conflicting previous evidence for pathogenicity: p.(Arg443Cys): Likely benign in ClinVar, VUS in LOVD3, PMID: 23396983, PMID: 28549997; p.(Arg443Pro): VUS in ClinVar and considered disease-causing in hypoplastic left heart syndrome (PMID: 27789736, PMID: 32656206 PMID: 29687901, PMID: 29697798). p.(Arg443Leu) has also been reported (PMID: 29420653). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS in ClinVar, citing PMID: 23861362; VUS in PMID: 31376648 and is listed as a rare variant in www.Cardiodb.org/Atlas of Cardiac Variation. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002470787	SCV003294644	uncertain significance	Hypertrophic cardiomyopathy 14	2022-10-05	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 MYH6 protein function. ClinVar contains an entry for this variant (Variation ID: 191720). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. This variant is present in population databases (rs202096001, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 443 of the MYH6 protein (p.Arg443His).
GeneDx	RCV000172032	SCV005369082	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	Has been reported as a variant of uncertain significance in an individual with sudden unexplained death who also harbored a second MYH6 variant, as well as a variant of uncertain significance in the SCN10A gene (Martinez-Matilla et al., 2019).; 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: 23861362, 31376648)