Submissions for variant NM_001271208.2(NEB):c.3416C>T (p.Thr1139Met) (rs181244403)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000297849	SCV000417018	uncertain significance	Nemaline Myopathy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000494005	SCV000581969	uncertain significance	not provided	2017-05-08	criteria provided, single submitter	clinical testing	The T1139M variant in the NEB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T1139M variant is observed in 3/11,544 (0.026%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The T1139M 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 in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T1139M as a variant of uncertain significance.
Invitae	RCV000641362	SCV000763003	uncertain significance	Nemaline myopathy 2	2017-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 1139 of the NEB protein (p.Thr1139Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs181244403, ExAC 0.03%). This variant has not been reported in the literature in individuals with NEB-related disease. ClinVar contains an entry for this variant (Variation ID: 331520). 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: "Not available"; 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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