Submissions for variant NM_002471.4(MYH6):c.4193G>A (p.Arg1398Gln)

gnomAD frequency: 0.00041  dbSNP: rs150815925

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172024	SCV000054808	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223030	SCV000272026	uncertain significance	not specified	2015-07-01	criteria provided, single submitter	clinical testing	The p.Arg1398Gln variant in MYH6 has been previously reported in 1 adult with ca rdiac dysrhythmia and 1 unaffected adult with a family history of DCM through a whole exome sequencing study (Gonzalez-Garay 2013). It has also been identified in 36/66590 European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs150815925). Computational prediction tools a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1398Gln varian t is uncertain.
Ambry Genetics	RCV000618730	SCV000737361	uncertain significance	Cardiovascular phenotype	2023-02-06	criteria provided, single submitter	clinical testing	The p.R1398Q variant (also known as c.4193G>A), located in coding exon 28 of the MYH6 gene, results from a G to A substitution at nucleotide position 4193. The arginine at codon 1398 is replaced by glutamine, an amino acid with highly similar properties. This variant has co-occurred with variants in other cardiac-related genes in an individual with atrial septal defect (Blue GM et al. J. Am. Coll. Cardiol. 2014 Dec;64(23):2498-506). This variant was detected in an individual reportedly affected with cardiomyopathy and cardiac dysrhythmia and also found in an unaffected individual with family history of cardiomyopathy (Gonzalez-Garay ML et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Oct;110:16957-62). This variant has also been reported in additional hypertrophic and dilated cardiomyopathy cohorts where, in several cases, it co-occurred with other variants in cardiac-related genes (Lopes LR et al. Heart, 2015 Feb;101:294-301; Bottillo I et al. Gene, 2016 Feb;577:227-35; Hertz CL et al. Int J Legal Med. 2016 Jan;130(1):91-102; Herkert JC et al. Genet Med. 2018 11;20(11):1374-1386; Asatryan B et al. Am J Cardiol. 2019 06;123(12):2031-2038). In addition, this variant has been published as a secondary cardiac variant of unknown significance in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). 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 variant remains unclear.
Invitae	RCV000647058	SCV000768845	uncertain significance	Hypertrophic cardiomyopathy 14	2024-01-24	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 1398 of the MYH6 protein (p.Arg1398Gln). This variant is present in population databases (rs150815925, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of MYH6-related conditions (PMID: 24082139, 26383259, 26656175, 29517769, 30847666, 30975432, 36178741). ClinVar contains an entry for this variant (Variation ID: 191712). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH6 protein function. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172024	SCV000884190	uncertain significance	not provided	2019-09-04	criteria provided, single submitter	clinical testing	The MYH6 c.4193G>A; p.Arg1398Gln variant (rs150815925) has been identified in at least three patients with some form of cardiomyopathy (Gonzalez-Garay 2013, Bottillo 2016, Pulignani 2018). This variant was also observed in one individual selected from a large cohort not selected for cardiomyopathy, and classified as uncertain based on population frequency (Ng 2013). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.07 percent in the East Asian population (identified on 20 out of 30,616 chromosomes) and has been reported to the ClinVar database (Variation ID: 191712). The arginine at position 1398 is highly conserved up to Opossum considering 5 species and computational analyses of the effects of the p.Arg1398Gln variant on protein structure and function provides conflicting results (SIFT: damaging, PolyPhen-2: benign). Thus, based on the available information, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223030	SCV000917838	uncertain significance	not specified	2018-09-11	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.4193G>A (p.Arg1398Gln) results in a conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 277100 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 15-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. The variant, c.4193G>A, has been reported in the literature in individuals affected with congenital heart disease and Cardiomyopathy (Bottillo_2015, Gonzalez-Garay_2013, Hertz_2016). Co-occurrences with other pathogenic variant(s) have been reported (MYH7 c.G428A, p.R143Q)(Bottillo_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171182	SCV001333874	likely benign	Cardiomyopathy	2018-03-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000172024	SCV002504131	uncertain significance	not provided	2023-08-15	criteria provided, single submitter	clinical testing	Reported in association with arrhythmia, sudden death, cardiomyopathy, atrial septal defect, and non-syndromic pulmonary stenosis (Gonzalez-Garay et al., 2013; Blue et al., 2014; Lopes et al., 2015; Bottillo et al., 2016; Hertz et al., 2016; Pulignani et al., 2018; Herkert et al., 2018; Van Lint et al., 2019; Asatryan 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: 29332214, 23861362, 28087566, 26383259, 25351510, 26350513, 30847666, 25500235, 30975432, 34426522, 29517769, 24082139, 26656175, 35621855)
CeGaT Center for Human Genetics Tuebingen	RCV000172024	SCV004010264	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	MYH6: PS4:Moderate, PP2, PP3, BP5
PreventionGenetics, part of Exact Sciences	RCV003947455	SCV004765198	uncertain significance	MYH6-related condition	2023-12-26	criteria provided, single submitter	clinical testing	The MYH6 c.4193G>A variant is predicted to result in the amino acid substitution p.Arg1398Gln. This variant has been reported in an individual with cardiac arrhythmia and an asymptomatic individual with a family history of cardiomyopathy (Table S8/S9 - Gonzalez-Garay et al. 2013. PubMed ID: 24082139). This variant has been reported in multiple individuals with cardiomyopathy (Bottillo et al. 2016. PubMed ID: 26656175; Hertz et al. 2016. PubMed ID: 26383259; Supplemental File 2, van Lint et al. 2019. PubMed ID: 30847666; Table S2, van der Meulen et al. 2022. PubMed ID: 36178741) and in an individual with sudden cardiac arrest (Asatryan et al. 2019. PubMed ID: 30975432). In at least two of these individuals the variant co-occurred with a pathogenic variant in different gene (Bottillo et al. 2016. PubMed ID: 26656175; Asatryan et al. 2019. PubMed ID: 30975432). Additionally, this variant was found in an individual with pulmonary stenosis (Pulignani et al. 2018. PubMed ID: 29332214). This variant is reported in 0.065% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations of likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/191712/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172024	SCV001744861	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172024	SCV001798505	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172024	SCV001920600	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172024	SCV001930313	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172024	SCV001975721	uncertain significance	not provided		no assertion criteria provided	clinical testing