ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.11798T>C (p.Met3933Thr) (rs772235127)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523635 SCV000619828 uncertain significance not provided 2017-08-10 criteria provided, single submitter clinical testing The M3933T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M3933T 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 where amino acids with similar properties to Methionine are tolerated across species. However, this 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. In silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000812877 SCV000953207 uncertain significance Nemaline myopathy 2 2018-08-31 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 3933 of the NEB protein (p.Met3933Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs772235127, ExAC 0.002%). This variant has not been reported in the literature in individuals with NEB-related disease. ClinVar contains an entry for this variant (Variation ID: 451165). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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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