Submissions for variant NM_002471.4(MYH6):c.4429C>T (p.Arg1477Cys)

dbSNP: rs201989347

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172023	SCV000054807	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461394	SCV000546138	uncertain significance	Hypertrophic cardiomyopathy 14	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1477 of the MYH6 protein (p.Arg1477Cys). This variant is present in population databases (rs201989347, gnomAD 0.006%). This missense change has been observed in individual(s) with MYH6-related conditions (PMID: 30847666, 34598319). ClinVar contains an entry for this variant (Variation ID: 191711). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH6 protein function with a positive predictive value of 80%. 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.
Ambry Genetics	RCV000620400	SCV000740240	uncertain significance	Cardiovascular phenotype	2022-11-07	criteria provided, single submitter	clinical testing	The p.R1477C variant (also known as c.4429C>T), located in coding exon 29 of the MYH6 gene, results from a C to T substitution at nucleotide position 4429. The arginine at codon 1477 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in a sudden cardiac arrest case and in cases with hypertrophic cardiomyopathy (HCM) or who underwent genetic testing for HCM (Asatryan B et al. Am J Cardiol, 2019 06;123:2031-2038; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Filatova EV et al. Mol Genet Genomic Med, 2021 11;9:e1808)). This alteration has also been reported as a secondary cardiac variant in an exome cohort and has been detected in an additional exome cohort not selected for the presence of cardiovascular disease; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Rodriguez-Flores JL et al. Hum Mutat, 2014 Jan;35:105-16). 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.
GeneDx	RCV000172023	SCV001812731	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with hypertrophic cardiomyopathy or sudden cardiac arrest in published literature (Asatryan et al., 2019; van Lint et al., 2019; Filatova et al., 2021); This variant is associated with the following publications: (PMID: 23861362, 22194935, 30975432, 30847666, 24123366, 34598319)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272157	SCV002557669	uncertain significance	Dilated cardiomyopathy 1EE	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 22194935). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 22194935). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v3: 8 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (highest allele count in v3: 7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin tail domain (DECIPHER). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Arg1477His), p.(Arg1477Leu) and p.(Arg1477Gly) have been classified as VUS by diagnostic laboratories in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It was identified in a male with sudden cardiac arrest and classified as a VUS (PMID: 30975432). This classification is supported by multiple diagnostic laboratories in ClinVar. (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
Fulgent Genetics, Fulgent Genetics	RCV002505238	SCV002814418	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-11-15	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000172023	SCV000925176	uncertain significance	not provided	2016-09-02	no assertion criteria provided	provider interpretation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172023	SCV001741666	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172023	SCV001800135	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172023	SCV001922472	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172023	SCV001932571	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172023	SCV001968901	uncertain significance	not provided		no assertion criteria provided	clinical testing