ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2508C>G (p.Ile836Met) (rs772442923)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234295 SCV000284265 uncertain significance Hypertrophic cardiomyopathy 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 836 of the MYH7 protein (p.Ile836Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 27247418). 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 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.
Ambry Genetics RCV000244256 SCV000318952 uncertain significance Cardiovascular phenotype 2015-08-03 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769456 SCV000900850 uncertain significance Cardiomyopathy 2017-04-03 criteria provided, single submitter clinical testing
Color RCV000769456 SCV001354119 uncertain significance Cardiomyopathy 2019-05-24 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223820 SCV000280325 uncertain significance not specified 2011-12-12 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. This variant is novel. This variant is located in coding exon 20. The isoleucine at codon 836 is replaced by methionine, an amino acid with highly similar properties. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation taster predicts this variant to be disease-causing. The Isoleucine at codon 836 is conserved across vertebrae species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (Lys835Thr; Pro838Leu). In total the variant has not been seen in ~6,500 laboratory controls and individuals from publicly available population datasets. There is no variation at codon 836 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/13/13). Note that this dataset does not match the patient's ancestry (Phillipines). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 9/13/13).

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