Submissions for variant NM_001271208.2(NEB):c.21442A>G (p.Met7148Val) (rs750039342)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498144	SCV000590125	uncertain significance	not provided	2017-06-05	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NEB gene. The M7148V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M7148V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved in mammals. However, the M7148V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000641393	SCV000763034	uncertain significance	Nemaline myopathy 2	2017-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with valine at codon 7148 of the NEB protein (p.Met7148Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs750039342, ExAC 0.05%). This variant has not been reported in the literature in individuals with NEB-related disease. ClinVar contains an entry for this variant (Variation ID: 432404). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.