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

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000641362	SCV000417018	uncertain significance	Nemaline myopathy 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
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	2019-11-26	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.
Natera, Inc.	RCV000641362	SCV001452174	uncertain significance	Nemaline myopathy 2	2020-01-17	no assertion criteria provided	clinical testing