Submissions for variant NM_001330260.2(SCN8A):c.4877G>A (p.Arg1626His)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000378250	SCV000344480	uncertain significance	not provided	2016-08-09	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000760191	SCV000890020	likely pathogenic	Cognitive impairment with or without cerebellar ataxia; Developmental and epileptic encephalopathy, 13; Seizures, benign familial infantile, 5	2017-04-25	criteria provided, single submitter	clinical testing
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV002287405	SCV002577669	pathogenic	Developmental and epileptic encephalopathy, 13	2022-10-04	criteria provided, single submitter	clinical testing	PS4_supporting;PM1;PM2_supporting;PM5;PM6;PP2;PP3;
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002287405	SCV002768665	pathogenic	Developmental and epileptic encephalopathy, 13	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 developmental and epileptic encephalopathy 13 (MIM#614558), respectively. In addition, gain of function is speculated for benign familial infantile seizures, 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 arginine to histidine. (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) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. p.(Arg1626Cys) and p.(Arg1626Leu) have been classified as pathogenic/likely pathogenic and VUS, respectively (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported de novo in at least three individuals with intellectual disability and seizures, or developmental and epileptic encephalopathy (PMID: 35701389; ClinVar). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518109	SCV002985437	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1626 of the SCN8A protein (p.Arg1626His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 35701389). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 290005). 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 SCN8A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Diagnostic Laboratory, Strasbourg University Hospital	RCV002274970	SCV002562869	uncertain significance	Abnormal cerebral morphology		no assertion criteria provided	clinical testing