ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5020G>A (p.Val1674Met) (rs397516235)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000628865 SCV000749773 uncertain significance Hypertrophic cardiomyopathy 2017-11-14 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1674 of the MYH7 protein (p.Val1674Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs397516235, ExAC 0.01%). This variant has been identified in an individual affected with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43052). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035946 SCV000059597 uncertain significance not specified 2012-06-14 criteria provided, single submitter clinical testing The Val1674Met variant in MYH7 has not been reported in the literature, but has been identified in 1 individual with HCM (this individual) out of >3600 probands (>2200 Caucasian) tested by our laboratory. In addition, this variant has not b een identified in large and broad populations (European and African American) se quenced by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS) . While this low frequency supports a pathogenic role, the ethnicity of this ind ividual was not specified and it remains possible that this variant is common in other populations. Valine (Val) at position 1674 is highly conserved in mammal and across evolutionarily distant species, though the change to methionine (Met) was predicted to be benign using a computational tool, which was validated by o ur laboratory using a set of cardiomyopathy variants with well-established clini cal significance (benign predictions are estimated to be correct 89% of the time , Jordan 2011). Additional studies are needed to fully assess the clinical signi ficance of this variant.

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