ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5534G>A (p.Arg1845Gln) (rs730880822)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158707 SCV000208642 likely pathogenic not provided 2013-02-14 criteria provided, single submitter clinical testing p.Arg1845Gln (CGG>CAG): c.5534 G>A in exon 37 of the MYH7 gene (NM_000257.2). The Arg1845Gln variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg1845Gln results in a semi-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Glutamine at a position that is conserved across species. In silico analysis predicts Arg1845Gln is damaging to the protein structure/function. Mutations at this codon (Arg1845Trp) and in nearby residues (Ser1836Leu, Arg1846Cys, Thr1854) have been reported in association with myopathy and cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the Arg1845Gln variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Arg1845Gln is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM panel(s).
Invitae RCV000686508 SCV000814029 uncertain significance Hypertrophic cardiomyopathy 2018-03-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1845 of the MYH7 protein (p.Arg1845Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 181286). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg1845Trp) has been determined to be pathogenic (PMID: 14520662, 17336526, 15699387, 17118657, 20376763, 19336582). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. 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.

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