ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5279C>T (p.Thr1760Met) (rs727505294)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156827 SCV000206548 uncertain significance not specified 2014-10-06 criteria provided, single submitter clinical testing The Thr1760Met variant in MYH7 has been reported in 2 Caucasian individuals with HCM and segregated with disease in 1 affected relative; however, 6 affected mem bers from the same family did not carry this variant (Fokstuen 2008, Calore 2011 ). It was absent from large population studies. Computational prediction tools a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Thr1760Met variant is uncertain due to conflicting evidence.
GeneDx RCV000767089 SCV000617013 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing The T1760M variant in the MYH7 gene has been reported previously in association with HCM in two unrelated individuals and was absent in approximately 500 controls, however, segregation studies were not performed (Fokstuen et al., 2008; Melacini et al, 2010). The T1760M variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The T1760M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, T1760M is classified in ClinVar as a variant of uncertain clinical significance by another clinical laboratory (SCV000206548.3; Landrum et al., 2016).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Phosphorus, Inc. RCV000577959 SCV000679786 uncertain significance Dilated cardiomyopathy 1S 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578016 SCV000679787 uncertain significance Familial hypertrophic cardiomyopathy 1 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578095 SCV000679788 uncertain significance Myopathy, distal, 1 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577955 SCV000679789 uncertain significance Myosin storage myopathy 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578035 SCV000679790 uncertain significance Myopathy, myosin storage, autosomal recessive 2017-08-01 criteria provided, single submitter clinical testing
Invitae RCV000702422 SCV000831276 uncertain significance Hypertrophic cardiomyopathy 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1760 of the MYH7 protein (p.Thr1760Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs727505294, ExAC 0.003%). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 18409188, 20513729). ClinVar contains an entry for this variant (Variation ID: 180024). 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"). 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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