Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000158726 | SCV000208661 | uncertain significance | not provided | 2012-08-23 | criteria provided, single submitter | clinical testing | p.Asp74Gly (GAC>GGC):c.221 A>G in exon 4 of the MYH7 gene (NM_000257.2). The Asp74Gly variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp74Gly results in a non-conservative amino acid substitution of a negatively charged Aspartic acid residue with a non-polar Glycine residue at a position that is conserved across species. However, in silico analysis predicts Asp74Gly is benign to the protein structure/function. Nevertheless, the NHLBI ESP Exome Variant Server reports Asp74Gly was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Asp74Gly is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s). |
| Invitae | RCV000698011 | SCV000826649 | uncertain significance | Hypertrophic cardiomyopathy | 2022-07-19 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 74 of the MYH7 protein (p.Asp74Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181298). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. |
| New York Genome Center | RCV003448273 | SCV004176201 | uncertain significance | Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1S | 2023-05-30 | criteria provided, single submitter | clinical testing | The c.221A>G p.(Asp74Gly) variant identified in the MYH7 gene has not been reported in affected individuals in the literature. It has been deposited to ClinVar database as a Varaint of Uncertain Significance [ClinVar ID:181298]. This variant is found in 1 out of ~590,000 alleles (0 homozygotes) in population databases (gnomAD v2.1.1, gnomAD v3.1.2, Top Med Freeze 8) suggesting that it is not a common benign variant in the populations represented in those databases. The c.221A>G variant in MYH7 is located in exon 4 of this 40-exon gene, and is predicted to replace an evolutionarily conserved aspartic acid residue with glycine at position 74 [p.(Asp74Gly)] in the head/motor domain of the encoded protein [PMID: 34935411, 30924982]. In silico predictions are inconclusive for the variant’s damaging effect [REVEL = 0.382]; however, functional studies to support or refute these predictions have not been reported. Given the lack of compelling evidence for its pathogenicity, the c.221A>G p.(Asp74Gly) variant identified in the MYH7 gene is reported as a Variant of Uncertain Significance. |