Submissions for variant NM_000334.4(SCN4A):c.52C>A (p.Arg18Ser)

gnomAD frequency: 0.00054  dbSNP: rs78592515

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000499480	SCV000596980	uncertain significance	not specified	2017-02-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545405	SCV000658598	uncertain significance	Hyperkalemic periodic paralysis	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 18 of the SCN4A protein (p.Arg18Ser). This variant is present in population databases (rs78592515, gnomAD 0.08%), including at least one homozygous and/or hemizygous individual. 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: 436668). 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.
GeneDx	RCV001584220	SCV001818699	uncertain significance	not provided	2024-05-09	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
Fulgent Genetics, Fulgent Genetics	RCV002490841	SCV002814022	uncertain significance	Hypokalemic periodic paralysis, type 1; Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16	2022-05-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000499480	SCV005040178	uncertain significance	not specified	2024-03-06	criteria provided, single submitter	clinical testing	Variant summary: SCN4A c.52C>A (p.Arg18Ser) results in a non-conservative amino acid change in 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 0.00038 in 247522 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in SCN4A causing Congenital Myopathy 22A, Classic (0.00038 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.52C>A in individuals affected with Congenital Myopathy 22A, Classic and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 436668). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breakthrough Genomics, Breakthrough Genomics	RCV001584220	SCV005193026	uncertain significance	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV001584220	SCV005412813	uncertain significance	not provided	2024-07-31	criteria provided, single submitter	clinical testing