ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1358G>T (p.Arg453Leu) (rs397516101)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000818531 SCV000959150 uncertain significance Hypertrophic cardiomyopathy 2019-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 453 of the MYH7 protein (p.Arg453Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 235026). 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 C0"). This variant disrupts the p.Arg453 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 11133230, 12975413, 17599605, 20031618 23283745, 24093860, 24111713), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 RCV000223878 SCV000280300 uncertain significance not specified 2015-06-02 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.Arg453Leu in MYH7 Based on the lack of data on this variant, we consider it a variant of uncertain significance. The online cardiogenomics database (curated by the Seidman group) notes that this variant was reported online by Haluza et al in 2000. I wasn’t able to find any further details or additional reports. The arginine at codon 453 is conserved across species, as are neighboring variants. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. There are two other variants at this codon (p.Arg453Cys, p.Arg453His). There is strong evidence supporting the pathogenicity of p.Arg453Cys and we consider it very likely disease causing. We currently classify p.Arg453His as likely disease causing. Variants at a nearby codon have been reported in association with cardiomyopathy (p.Lys450Glu, p.Lys450Thr). There is no variation at codon 453 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/14/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/14/2012). ***The variant was not observed in published controls: ***.

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