Submissions for variant NM_003803.4(MYOM1):c.4357A>T (p.Met1453Leu) (rs181642354)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000216488	SCV000272174	uncertain significance	not specified	2016-01-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Met1453Leu va riant in MYOM1 has not been previously reported in individuals with cardiomyopat hy, but has been identified in 5/19248 European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs181642354). Methi onine (Met) at position 1453 is not conserved in mammals or evolutionarily dista nt species, raising the possibility that a change at this position may be tolera ted. In summary, while the clinical significance of the p.Met1453Leu variant is uncertain, these data suggest that it is more likely to be benign.
Invitae	RCV000804278	SCV000944180	uncertain significance	Hypertrophic cardiomyopathy	2019-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with leucine at codon 1453 of the MYOM1 protein (p.Met1453Leu). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs181642354, ExAC 0.03%). This variant has not been reported in the literature in individuals with MYOM1-related disease. ClinVar contains an entry for this variant (Variation ID: 229026). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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