Submissions for variant NM_000334.4(SCN4A):c.4949C>T (p.Pro1650Leu)

gnomAD frequency: 0.00002  dbSNP: rs774183791

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000713119	SCV000843690	uncertain significance	not provided	2018-08-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001224260	SCV001396447	likely pathogenic	Hyperkalemic periodic paralysis	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1650 of the SCN4A protein (p.Pro1650Leu). This variant is present in population databases (rs774183791, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive SCN4A-related conditions (PMID: 30369941, 32487525). ClinVar contains an entry for this variant (Variation ID: 586523). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN4A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 32487525). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV000713119	SCV001830671	uncertain significance	not provided	2020-03-27	criteria provided, single submitter	clinical testing	Observed in an individual with neuromuscular symptoms who harbored a second SCN4A variant (Theunissen et al., 2018); 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: 32487525, 32129495, 30369941)
Fulgent Genetics, Fulgent Genetics	RCV005004385	SCV002776152	uncertain significance	Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16; Congenital myopathy 22A, classic; Congenital myopathy 22B, severe fetal	2024-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000713119	SCV004138783	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing	SCN4A: PM2, PM3, PP3