ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1532T>C (p.Ile511Thr) (rs397516110)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035729 SCV000059380 uncertain significance not specified 2016-02-03 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ile511Thr variant in MYH7 has been reported 1 individual with HCM (Van Driest 2004) and 1 individual with biventricular hypertrophy and Down syndrome (LMM unpublished da ta) and was absent from large population studies. This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (J ordan 2011). In summary, while there is some suspicion for a pathogenic role, th e clinical significance of the p.Ile511Thr variant is uncertain.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201470 SCV000256143 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV000795739 SCV000935210 uncertain significance Hypertrophic cardiomyopathy 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 511 of the MYH7 protein (p.Ile511Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 24093860, 27247418). ClinVar contains an entry for this variant (Variation ID: 42848). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Ile511 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15563892), which suggests that this may be a clinically significant amino acid residue. 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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