Submissions for variant NM_001330260.2(SCN8A):c.5615G>A (p.Arg1872Gln)

dbSNP: rs796053229

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen	RCV003992248	SCV005061733	pathogenic	Complex neurodevelopmental disorder	2024-05-09	reviewed by expert panel	curation	The c.5615G>A variant in SCN8A is a missense variant predicted to cause a subtitution of arginine by glutamine at amino acid 1872 (p.Arg1872Gln). This variant has been reported as de novo in at least 3 individuals with unconfirmed parental relationships (PMIDs: 2664715, 28333917, 28387369) (PM6) and at least an additional 8 individuals without informative segregation data available (PMIDs: 25568300, 29655203, 29930392, 32509551, 34395220, 30968951) (PS4). Multiple other amino acid substitutions at the same amino acid position have been previously reported and meet pathogenic per these criteria (p.Arg1872Gly, p.Arg1872Trp, p.Arg1872Leu) (PM5). Heterologous expression with voltage clamping assay has shown significant hyperpolarizing shift in voltage dependence of activation and significant depolarizing shift of voltage dependence of fast inactivation (PS3). The variant is rare (1 allele) in the population database, gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM6, PM5, PS3, PM2_Supporting (version 1.0; approved 5/23/23).
GeneDx	RCV000523884	SCV000617110	pathogenic	not provided	2020-05-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate hyperactivity of the sodium channel by impairing channel inactivation (Wagnon et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This substitution is predicted to be within the C-terminal cytoplasmic domain; This variant is associated with the following publications: (PMID: 26029160, 24194747, 25568300, 26647175, 26900580, 28387369, 29574705, 29100083, 28333917, 30968951, 30185235, 31077350, 30552426, 32090326, 32509551)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704631	SCV000833587	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-07-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1872 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24888894, 25951352, 26029160, 26900580, 27779742). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SCN8A function (PMID: 26900580). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 253297). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 25568300, 26647175, 26900580, 28387369). In at least one individual the variant was observed to be de novo. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1872 of the SCN8A protein (p.Arg1872Gln).
Baylor Genetics	RCV000239745	SCV001522182	pathogenic	Developmental and epileptic encephalopathy, 13	2019-10-24	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Centogene AG - the Rare Disease Company	RCV000239745	SCV002059441	pathogenic	Developmental and epileptic encephalopathy, 13	2021-05-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005008215	SCV005637313	pathogenic	Cognitive impairment with or without cerebellar ataxia; Developmental and epileptic encephalopathy, 13; Seizures, benign familial infantile, 5; Myoclonus, familial, 2	2024-02-20	criteria provided, single submitter	clinical testing
GeneReviews	RCV000239745	SCV000298216	not provided	Developmental and epileptic encephalopathy, 13		no assertion provided	literature only
Channelopathy-Associated Epilepsy Research Center	RCV003992248	SCV004809229	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only