Submissions for variant NM_001271208.2(NEB):c.25270C>T (p.Arg8424Trp) (rs373551215)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000536760	SCV000416809	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	RCV000521206	SCV000619360	uncertain significance	not provided	2017-07-20	criteria provided, single submitter	clinical testing	The R8424W variant in the NEB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R8424W variant is observed in 10/12108 (0.08%) alleles from individuals of South Asian background, in the ExAC dataset (Lek et al., 2016). The R8424W 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 across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R8424W as a variant of uncertain significance.
Invitae	RCV000536760	SCV000640753	uncertain significance	Nemaline myopathy 2	2017-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 8424 of the NEB protein (p.Arg8424Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs373551215, ExAC 0.08%). This variant has not been reported in the literature in individuals with an NEB-related disease. ClinVar contains an entry for this variant (Variation ID: 331403). 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";  Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on NEB function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV000536760	SCV001454424	uncertain significance	Nemaline myopathy 2	2020-01-17	no assertion criteria provided	clinical testing