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

dbSNP: rs1057518801

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen	RCV003243119	SCV005061728	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-05-09	reviewed by expert panel	curation	The c.2624T>C variant in SCN3A is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 875 (p.Ile875Thr). The variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) with DEE (PMIDs: 29740860, 29466837) (PS2_Very Strong) and as a de novo occurrance with unconfirmed parental relationship in a least 2 individuals with DEE (PMIDs: 29286531, 28191890) (PM6_Moderate), with additional case evidence available in the literature. The variant is absent from gnomAD v2.1.1 (PM2_Supporting). Studies have observed that when expressed in mammalian cells in culture, this variant causes a gain-of-function effect on the mutant channels as evidenced by a significant leftward/hyperpolarized shift in the voltage dependence of activation, an increase in the persistent/inactivating current, and a rightward/depolarizing shift in the voltage of inactivation (PS3; PMID: 29466837). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant developmental and epilepstic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2_VS, PM6_Moderate, PM2_Supporting, PS3. (Version 1; July 7, 2023).
GeneDx	RCV000494116	SCV000581932	pathogenic	not provided	2025-03-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29466837, 28135719, 29286531, 28191890, 30904718, 29740860, 30146301, 32090326, 32515017, 31785789, 33057194, 35982159, 38259611, 37935051)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000494116	SCV000944165	pathogenic	not provided	2024-11-21	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with polymicrogyria and early infantile epileptic encephalopathy (PMID: 29466837, 29740860; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 373960). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN3A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN3A function (PMID: 29466837). For these reasons, this variant has been classified as Pathogenic.
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
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798831	SCV005420595	pathogenic	Epilepsy	2024-10-04	criteria provided, single submitter	research	PS2,PS3,PM2,PP3
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)
Channelopathy-Associated Epilepsy Research Center	RCV003243119	SCV004809309	not provided	Early infantile epileptic encephalopathy with suppression bursts		no assertion provided	literature only