Submissions for variant NM_000334.4(SCN4A):c.1333G>C (p.Val445Leu)

gnomAD frequency: 0.00001  dbSNP: rs121908552

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000516348	SCV000615061	likely pathogenic	not provided	2023-04-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with myotonia. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging.
Invitae	RCV000559054	SCV000658516	pathogenic	Hyperkalemic periodic paralysis	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 445 of the SCN4A protein (p.Val445Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant myotonia congenita (PMID: 27199537; Invitae). ClinVar contains an entry for this variant (Variation ID: 448262). 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 with a positive predictive value of 95%. This variant disrupts the p.Val445 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9392583, 22653516, 25724373, 25839108). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000516348	SCV001784005	likely pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25724373, 22653516, 9392583, 25839108, 33965302, 27199537, 34908252)
Revvity Omics, Revvity	RCV000516348	SCV003818648	uncertain significance	not provided	2019-09-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003403223	SCV004103242	likely pathogenic	SCN4A-related condition	2023-03-15	criteria provided, single submitter	clinical testing	The SCN4A c.1333G>C variant is predicted to result in the amino acid substitution p.Val445Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An alternate G-to-A nucleotide change and a G-to-T nucleotide change at the same nucleotide position (c.1333) have been reported in individuals with autosomal dominant myotonia (c.1333G>A (p.Val445Met) and c.1333G>T (p.Val445Leu); Rosenfeld et al. 1997. PubMed ID: 9392583; Table 3, Sun et al. 2019. PubMed ID: 31567646; Table 2, Maggi et al. 2020. PubMed ID: 32849172; Table 4, Vereb. 2020. PubMed ID: 33263785; Table 3, Babić Božović et al. 2021. PubMed ID: 34106991; ClinVar Variation IDs: 5910 and 373945). The c.1333G>C (p.Val445Leu) variant is interpreted as likely pathogenic.