Submissions for variant NM_006922.4(SCN3A):c.2624T>C (p.Ile875Thr)

dbSNP: rs1057518801

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494116	SCV000581932	likely pathogenic	not provided	2015-08-21	criteria provided, single submitter	clinical testing	The I875T variant in the SCN3A gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The I875T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I875T 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 occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The I875T variant is a strong candidate for a disease-causing variant, however, the possibility it may be a rare benign variant cannot be excluded.
Invitae	RCV000494116	SCV000944165	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with polymicrogyria and early infantile epileptic encephalopathy (PMID: 29466837, 29740860; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 875 of the SCN3A protein (p.Ile875Thr). ClinVar contains an entry for this variant (Variation ID: 373960). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN3A function (PMID: 29466837). 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 SCN3A protein function.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199328	SCV001370411	likely pathogenic	Epilepsy, familial focal, with variable foci 4	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. This variant arose de novo in at least one reported proband.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000494116	SCV001447447	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001199328	SCV001519700	pathogenic	Epilepsy, familial focal, with variable foci 4	2020-05-29	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Institute of Human Genetics, University of Leipzig Medical Center	RCV000625712	SCV002044406	likely pathogenic	Developmental and epileptic encephalopathy, 62	2021-12-21	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000625712	SCV002768604	pathogenic	Developmental and epileptic encephalopathy, 62	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Loss of function effects have been shown to be associated with focal epilepsy whilst gain of function effects have been shown to be associated with epileptic encephalopathy (PMID: 29466837, 28235671). (N) 0200 - Variant is predicted to result in a missense amino acid change from an isoleucine to a threonine (exon 17). (N) 0251 - Variant is heterozygous. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0301 - Variant is absent from gnomAD. (P) 0600 - Variant is located in an annotated domain or motif (S4-S5 linker of ion transport domain II (PMID: 30146301, 29466837)). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported de novo in patients with epileptic encephalopathy with cerebral cortical development malformations (ClinVar; Decipher; PMID: 29740860, 30146301, 29466837, 30904718). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Cell lines expressing this variant demonstrated gain of function effects (PMID: 30146301, 29466837). (P) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV003243119	SCV003936814	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-07-05	criteria provided, single submitter	clinical testing
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000625712	SCV004014851	pathogenic	Developmental and epileptic encephalopathy, 62	2023-07-20	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415038	SCV000492610	likely pathogenic	Polymicrogyria; Developmental delay	2016-05-13	no assertion criteria provided	clinical testing
OMIM	RCV000625712	SCV000746212	pathogenic	Developmental and epileptic encephalopathy, 62	2020-11-17	no assertion criteria provided	literature only
GeneReviews	RCV001199328	SCV001737417	not provided	Epilepsy, familial focal, with variable foci 4		no assertion provided	literature only	Most common recurrent pathogenic variant; associated with treatment-resistant seizures, severe/profound developmental delay/intellectual disability, and malformation of cortical development (pachy- or polymicrogyria)