Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000533350 | SCV000658577 | uncertain significance | Hyperkalemic periodic paralysis | 2022-04-09 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 477421). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. This variant is present in population databases (rs375844960, gnomAD 0.007%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1424 of the SCN4A protein (p.Val1424Ile). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317279 | SCV004020564 | uncertain significance | not specified | 2023-06-01 | criteria provided, single submitter | clinical testing | Variant summary: SCN4A c.4270G>A (p.Val1424Ile) results in a conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247904 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4270G>A in individuals affected with Acetazolamide-Responsive Myotonia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |