ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1405G>A (p.Asp469Asn) (rs397516106)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154581 SCV000204254 uncertain significance not specified 2013-02-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000766422 SCV000208738 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing The D469N mutation in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. However, a mutation affecting this same residue, D469Y, has been reported in association with DCM (Lakdawala N et al., 2012) and mutations in nearby residues (I467L, I467T, F468L, Q475H, Q475K) have been reported in association with cardiomyopathy, further supporting the functional importance of this residue and this region of the protein. D469N results in a non-conservative amino acid substitution of a negatively-charged Aspartic Acid with a neutral, polar Asparagine at a position that is highly conserved across species. In addition, the D469N mutation was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Invitae RCV001054042 SCV001218335 uncertain significance Hypertrophic cardiomyopathy 2019-02-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 469 of the MYH7 protein (p.Asp469Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs397516106, ExAC 0.001%). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177921). 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: "Probably Damaging"; Align-GVGD: "Class C15"). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000154581 SCV000280301 uncertain significance not specified 2012-03-05 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp469Asn (c.1405 G>A) in MYH7 The variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.999). The aspartic acid at codon 469 is completely conserved across species, and neighboring amino acids are highly conserved. I could find one nearby variant reported in association with disease, p.Ile462Phe. The variant was reported online in 1 of 61439 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/ as of November 29th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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