Submissions for variant NM_001165963.4(SCN1A):c.4916G>C (p.Arg1639Pro)

dbSNP: rs796053029

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen	RCV004577517	SCV005061719	pathogenic	Severe myoclonic epilepsy in infancy	2024-05-09	reviewed by expert panel	curation	The c.4916G>C variant in SCN1A is a missense variant predicted to cause substitution of arginine by proline at amino acid 1639 (p.Arg1639Pro). This variant has been reported in at least one individual with Dravet syndrome and another individual with epilepsy with no additional details (PMIDs:35087721, 29655203) (PS4_Moderate). Multiple missense variants in SCN1A and in paralogous genes have previously been reported and meet P/LP per these criteria, including SCN1A: p.R1639G (PMIDs:18930999), SCN2A: p.R1629L, p.R1629H and SCN8A: p.R1620L (PMIDs 28330790, 3061509). (PM5_Strong). An identical amino acid substitution at the corresponding position in the paralogous gene, SCN2A has been reported as de novo (p.R1629P), however this did not meet P/LP per these criteria so PS1 was not met. This variant is absent from the population database, gnomAD v2.1.1 (PM2_Supporting). It falls within a pathogenic enriched region that is defined as a mutational hotspot (PM1). The computational predictor REVEL gives a score of 0.98, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant Dravet syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4_Moderate, PM5_Strong, PM1, PM2_Supporting, PP3_Moderate (version 1.0; 5/9/23).
GeneDx	RCV000188984	SCV000242615	likely pathogenic	not provided	2018-05-23	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the SCN1A gene. The R1639P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1639P variant is not observed in large population cohorts (Lek et al., 2016). The R1639P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution is predicted to be within the transmembrane segment S4 of the fourth homologous domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with SCN1A-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244268	SCV001417476	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2022-11-22	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) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. ClinVar contains an entry for this variant (Variation ID: 206852). This missense change has been observed in individual(s) with epilepsy and/or neurodevelopmental delay (PMID: 29655203). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1639 of the SCN1A protein (p.Arg1639Pro).