Submissions for variant NM_002471.4(MYH6):c.4082G>A (p.Arg1361His)

gnomAD frequency: 0.00004  dbSNP: rs533942127

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156402	SCV000206120	uncertain significance	not specified	2021-03-31	criteria provided, single submitter	clinical testing	The p.Arg1361His variant in MYH6 has been reported in 1 individual with HCM (Lopes 2015 PMID: 25351510). It has also been identified in 0.008% (2/24960) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported as a variant of uncertain significance in ClinVar (Variation ID 179607). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3.
Ambry Genetics	RCV000620200	SCV000740234	uncertain significance	Cardiovascular phenotype	2023-03-16	criteria provided, single submitter	clinical testing	The p.R1361H variant (also known as c.4082G>A), located in coding exon 27 of the MYH6 gene, results from a G to A substitution at nucleotide position 4082. The arginine at codon 1361 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000156402	SCV001361610	uncertain significance	not specified	2019-10-07	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.4082G>A (p.Arg1361His) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251410 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4082G>A has been reported in the literature in at-least two cases of individuals affected with Hypertrophic Cardiomyopathy (HCM) (Walsh_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrence with another pathogenic variant(s) has been observed at our laboratory (MYH7 c.2539A>G, p.Lys847Glu), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001209675	SCV001381121	uncertain significance	Hypertrophic cardiomyopathy 14	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1361 of the MYH6 protein (p.Arg1361His). This variant is present in population databases (rs533942127, gnomAD 0.008%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510, 28082330). ClinVar contains an entry for this variant (Variation ID: 179607). 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.
GeneDx	RCV001357313	SCV001820552	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	Identified in association with HCM in published literature (PMID: 25351510, 28082330); 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: 28082330, 25351510)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272144	SCV002557041	uncertain significance	Atrial septal defect 3	2022-06-24	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. GoF has been suggested for specific missense variants (PMID: 20656787). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 22194935). (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 (v2) <0.001 for a dominant condition (9 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 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) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been identified in a hypertrophic cardiomyopathy cohort (PMID: 25351510). It is also reported multiple times as a VUS in ClinVar, and once as likely benign in LOVD. (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) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002505177	SCV002798225	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-12-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001357313	SCV003809572	uncertain significance	not provided	2021-07-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001357313	SCV004226494	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	PP3
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357313	SCV001552748	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYH6 p.Arg1361His variant was identified in 1 of 1748 proband chromosomes (frequency 0.000572) from individuals with hypertrophic cardiomyopathy (Lopes_2014_ PMID:25351510). The variant was identified in dbSNP (ID: rs533942127) and ClinVar (classified as uncertain significance by Ambry and the Laboratory for Molecular Medicine). The variant was also identified in LOVD 3.0 where it was classified as likely benign. The variant was identified in control databases in 9 of 282790 chromosomes at a frequency of 0.00003183 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 2 of 24960 chromosomes (freq: 0.00008), East Asian in 1 of 19952 chromosomes (freq: 0.00005), South Asian in 1 of 30616 chromosomes (freq: 0.000033), European (non-Finnish) in 4 of 129126 chromosomes (freq: 0.000031) and Latino in 1 of 35436 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, European (Finnish), or Other populations. The p.Arg1361 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.