ClinVar Miner

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

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Total submissions: 2
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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.

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