Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000713100 | SCV000843670 | pathogenic | not provided | 2016-07-25 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001210018 | SCV001381482 | pathogenic | Hyperkalemic periodic paralysis | 2022-12-25 | criteria provided, single submitter | clinical testing | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN4A protein function. Experimental studies have shown that this missense change affects SCN4A function (PMID: 14557559, 17898326). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5917). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1158 of the SCN4A protein (p.Pro1158Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with myotonia congenita (PMID: 10851391, 21221019). It has also been observed to segregate with disease in related individuals. |
| Gene |
RCV000713100 | SCV003194923 | pathogenic | not provided | 2024-03-18 | criteria provided, single submitter | clinical testing | Observed in affected individuals with myotonia in several unrelated families in published literature. Additional individuals within these same families also share a similar phenotype suggesting autosomal dominant inheritance, however segregation data could not be confirmed (PMID: 10851391, 29606556); Published functional studies demonstrate a damaging effect resulting in SCN4A, the alpha subunit of the sodium channel, having greater sensitivity to pH and temperature changes (PMID: 29674667, 14557559); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25454733, 17898326, 16193245, 16195244, 14557559, 33836525, 34027742, Ghovanloo2021, 21221019, 26986070, 33325393, 32527974, 28940424, 18337730, 10851391, 29606556, 29674667) |
| Ambry Genetics | RCV002512825 | SCV003579323 | pathogenic | Inborn genetic diseases | 2021-11-08 | criteria provided, single submitter | clinical testing | The c.3472C>T (p.P1158S) alteration is located in exon 19 (coding exon 19) of the SCN4A gene. This alteration results from a C to T substitution at nucleotide position 3472, causing the proline (P) at amino acid position 1158 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported to segregate with disease in multiple families with myotonia and periodic paralysis (Sugiura, 2000; Modoni, 2011). In addition, alterations affecting the same amino acid, p.P1158L and p.P1158A, have been reported in patients with myotonia (Desaphy 2016; Xu, 2018). Patch clamp experiments showed temperature-dependent negative shifts in the voltage dependence of activation and inactivation as well as a slower rate of inactivation for the P1158S channels as compared to wild type channels (Sugiura, 2003). Voltage-clamp studies of Na currents showed that wildtype and P1158S channels displayed comparable behavior at 37 °C, but upon cooling to 25 °C, mutant channels activated at more negative potentials and slow inactivation was destabilized (Webb, 2008). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
| OMIM | RCV000006280 | SCV000026462 | pathogenic | Hypokalemic periodic paralysis, type 2 | 2003-10-14 | no assertion criteria provided | literature only |