ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2420G>A (p.Arg807His)

gnomAD frequency: 0.00002  dbSNP: rs141414377
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000428391 SCV000535073 uncertain significance not specified 2016-12-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The R807H variant has not been published as pathogenic or been reported as benign to our knowledge. The R807H variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, R807H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000584770 SCV000692527 likely pathogenic Hypertrophic cardiomyopathy 2018-06-14 criteria provided, single submitter research MYH7 Arg807His has been reported in 2 other HCM probands (Erdmann J, et al., 2003) and is present at low frequency in Exome Aggregation Consortium dataset (MAF=0.000008; http://exac.broadinstitute.org/). We identified this variant in a HCM proband with no family history of disease or sudden cardiac death. The proband also harbours a pathogenic MYH7 variant (p.Ala797Thr) in trans. In silico tools SIFT, PolyPhen2, PolyPhen-HCM and MutationTaster predict this variant to be deleterious. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) the variant is located in a known functional domain of MYH7 (PM1), is rare in the general population (PM2), is predicted to be deleterious by multiple in silico tools (PP3) and has been identified in at least 3 HCM probands (PS4_supporting), therefore we classify MYH7 Arg807His as 'likely pathogenic'.
Color Diagnostics, LLC DBA Color Health RCV001180607 SCV001345573 uncertain significance Cardiomyopathy 2023-03-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 807 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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: 28790153, 32228044) and in an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 4/282844 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 RCV000584770 SCV001558656 uncertain significance Hypertrophic cardiomyopathy 2023-08-04 criteria provided, single submitter clinical testing 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. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 807 of the MYH7 protein (p.Arg807His). This variant is present in population databases (rs141414377, gnomAD 0.006%). This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 28790153, 31983221). ClinVar contains an entry for this variant (Variation ID: 391904). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 RCV002446751 SCV002732863 uncertain significance Cardiovascular phenotype 2022-03-17 criteria provided, single submitter clinical testing The p.R807H variant (also known as c.2420G>A), located in coding exon 19 of the MYH7 gene, results from a G to A substitution at nucleotide position 2420. The arginine at codon 807 is replaced by histidine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been reported in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited, and at least one individual had a co-occurring MYH7 pathogenic variant (Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print; Marstrand P et al. Circulation, 2020 04;141:1371-1383; Mazzarotto F et al. Circulation, 2020 02;141:387-398). This amino acid position is well 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.
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University RCV003319198 SCV003932379 pathogenic Dilated cardiomyopathy 1S 2023-06-01 criteria provided, single submitter clinical testing

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