Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000540718 | SCV000640862 | uncertain significance | Nemaline myopathy 2 | 2019-11-20 | criteria provided, single submitter | clinical testing | This sequence change deletes 2 nucleotides and inserts 2 nucleotides in exon 10 of the NEB mRNA (c.771_772delinsCA), replacing aspartic acid with asparagine at codon 258 of the NEB protein (p.Asp258Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is reported as two separate single-nucleotide changes in the ExAC database (c.771T>C and c.772G>A), but the read data shows that the two variants are in cis, recapitulating the variant observed here (c.771_772delinsCA), in at least 4 individuals. It has not been reported in the literature in individuals with an NEB-related disease. 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. |