Submissions for variant NM_000334.4(SCN4A):c.3682G>A (p.Asp1228Asn)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002937937	SCV003263011	uncertain significance	Hyperkalemic periodic paralysis	2023-07-03	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. 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) has been performed at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 2053078). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. This variant is present in population databases (rs772250087, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1228 of the SCN4A protein (p.Asp1228Asn).
Revvity Omics, Revvity	RCV003138394	SCV003821261	uncertain significance	not provided	2023-02-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003170584	SCV003895627	uncertain significance	Inborn genetic diseases	2023-02-15	criteria provided, single submitter	clinical testing	The c.3682G>A (p.D1228N) alteration is located in exon 19 (coding exon 19) of the SCN4A gene. This alteration results from a G to A substitution at nucleotide position 3682, causing the aspartic acid (D) at amino acid position 1228 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403959	SCV004122167	uncertain significance	not specified	2023-10-26	criteria provided, single submitter	clinical testing	Variant summary: SCN4A c.3682G>A (p.Asp1228Asn) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248942 control chromosomes. 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.3682G>A in individuals affected with Acetazolamide-Responsive Myotonia and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005019470	SCV005651730	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	2024-06-10	criteria provided, single submitter	clinical testing