ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3622G>A (p.Asp1208Asn) (rs730880781)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208329 SCV000264087 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-03-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621190 SCV000740163 uncertain significance Cardiovascular phenotype 2017-05-25 criteria provided, single submitter clinical testing The p.D1208N variant (also known as c.3622G>A), located in coding exon 25 of the MYH7 gene, results from a G to A substitution at nucleotide position 3622. The aspartic acid at codon 1208 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. <br />
Invitae RCV000804739 SCV000944662 uncertain significance Hypertrophic cardiomyopathy 2020-09-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1208 of the MYH7 protein (p.Asp1208Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 27532257, 23396983, Invitae). ClinVar contains an entry for this variant (Variation ID: 222725). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). This variant disrupts the p.Asp1208 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 29398688), which suggests that this may be a clinically significant amino acid residue. 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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