Submissions for variant NM_000334.4(SCN4A):c.386T>C (p.Ile129Thr)

gnomAD frequency: 0.00005  dbSNP: rs369652972

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001302073	SCV001491266	uncertain significance	Familial hyperkalemic periodic paralysis	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 129 of the SCN4A protein (p.Ile129Thr). This variant is present in population databases (rs369652972, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1005233). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN4A protein function. 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.
Fulgent Genetics, Fulgent Genetics	RCV005005145	SCV002784457	uncertain significance	Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Familial hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16; Congenital myopathy 22A, classic; Congenital myopathy 22B, severe fetal	2024-02-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002539492	SCV003540324	uncertain significance	Inborn genetic diseases	2022-02-11	criteria provided, single submitter	clinical testing	The c.386T>C (p.I129T) alteration is located in exon 2 (coding exon 2) of the SCN4A gene. This alteration results from a T to C substitution at nucleotide position 386, causing the isoleucine (I) at amino acid position 129 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV003135936	SCV003821320	uncertain significance	not provided	2023-11-28	criteria provided, single submitter	clinical testing
GeneDx	RCV003135936	SCV005396717	uncertain significance	not provided	2024-05-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Athena Diagnostics	RCV003135936	SCV005622570	uncertain significance	not provided	2024-11-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004727104	SCV005338290	uncertain significance	SCN4A-related disorder	2024-09-25	no assertion criteria provided	clinical testing	The SCN4A c.386T>C variant is predicted to result in the amino acid substitution p.Ile129Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0086% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.