Submissions for variant NM_001330260.2(SCN8A):c.4426G>A (p.Gly1476Ser)

dbSNP: rs1064793263

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480970	SCV000565539	likely pathogenic	not provided	2014-03-26	criteria provided, single submitter	clinical testing	A novel G1476S variant that is likely pathogenic has been identified in the SCN8A gene. The G1476S variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,200 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The G1476S 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 alters a highly conserved position in the cytoplasmic loop between the third and forth homologous domains. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Mendelics	RCV000988848	SCV001138737	likely pathogenic	Developmental and epileptic encephalopathy, 13	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001856819	SCV002187395	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2022-07-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 418482). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1476 of the SCN8A protein (p.Gly1476Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epilepsy and/or a neurodevelopmental disorder (PMID: 29655203). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000988848	SCV002557278	likely pathogenic	Developmental and epileptic encephalopathy, 13	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with cognitive impairment with or without cerebellar ataxia (MIM#614306) and Epileptic encephalopathy, early infantile, 13 (MIM#614558), respectively. In addition, gain of function is speculated for seizures, benign familial infantile, 5 (MIM#617080) (PMID: 31904124, OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Gly1476Asp) has been identified in a family with two affected individuals who presented with early-onset infantile epilepsy without intellectual disability and neurological deficits (PMID: 29263050). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals with SCN8A-related epilepsy and neurodevelopmental disorders (ClinVar, PMID: 29655203). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign