Submissions for variant NM_000252.2(MTM1):c.1406A>G (p.His469Arg) (rs587783789)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory,University of Chicago	RCV000146411	SCV000193697	pathogenic	Severe X-linked myotubular myopathy	2013-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV000146411	SCV000634487	uncertain significance	Severe X-linked myotubular myopathy	2017-04-29	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with arginine at codon 469 of the MTM1 protein (p.His469Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with X-linked myotubular myopathy (PMID: 17537630). ClinVar contains an entry for this variant (Variation ID: 158932). 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 different missense substitution at this codon (p.His469Pro) has been reported in an affected individual, but the clinical significance of this observation is unknown (PMID: 9305655). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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