Submissions for variant NM_001165963.4(SCN1A):c.5347G>A (p.Ala1783Thr)

dbSNP: rs121917980

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Bioinformatics, Peking University	RCV000059445	SCV000221768	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
GeneDx	RCV000188999	SCV000242630	pathogenic	not provided	2017-08-17	criteria provided, single submitter	clinical testing	p.Ala1783Thr (GCG>ACG): c.5347 G>A in exon 26 of the SCN1A gene (NM_001165963.1) The A1783T missense mutation in the SCN1A gene has been reported previously as a de novo mutation in association with Dravet syndrome and other SCN1A-related disorders (for examples, see Harkin et al., 2007; Sun et al., 2010; Heron et al., 2010). This mutation alters a highly conserved position predicted to be within the transmembrane segment S6 of the fourth homologous domain of the SCN1A protein, and another missense mutation at the same codon (A1783V) has also been published in association with SCN1A-related disorders in an external mutation database. The A1783T substitution 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. The variant is found in EPILEPSY,CHILD-EPI panel(s).
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV000059445	SCV001167095	pathogenic	Severe myoclonic epilepsy in infancy	2018-10-31	criteria provided, single submitter	clinical testing	p.Ala1783Thr (GCG>ACG): c.5347 G>A in exon 26 of the SCN1A gene (NM_001165963.1). A heterozygous missense variant was identified in a patient with Dravet syndrome. It involves a change of Guanine for Adenine at position 5347 of the coding DNA, which is located in exon 26 of the gene and generates a change from Alanine to Threonine (p .Ala1783Thr) at the protein level. This variant was described in 2007 by Harkin et al (Brain. 2007 Mar; 130 (Pt 3): 843-5) associated with Dravet syndrome and it is reported as pathogenic in the following databases: i) HGMD, ii) Ensembl, iii) ClinVar. According to the ACMG criteria, the variant was classified as pathogenic (PS2, PS3, PM1, PM2, PP2, PP3, PP4, PP5). The variant was confirmed by capillary sequencing (Sanger) in the index case. Sanger sequencing searching for this variant was performed on both parents giving a negative result, so it is presumed to be a de novo variant.
CeGaT Center for Human Genetics Tuebingen	RCV000188999	SCV001245862	pathogenic	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001240035	SCV001412956	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1783 of the SCN1A protein (p.Ala1783Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe myoclonic epilepsy of infancy and Dravet syndrome (PMID: 17347258, 30321769). In at least one individual the variant was observed to be de novo. This variant is also known as 5314G>A (Ala1772Thr). ClinVar contains an entry for this variant (Variation ID: 68570). 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 SCN1A protein function. For these reasons, this variant has been classified as Pathogenic.
DASA	RCV001849308	SCV002107108	pathogenic	Generalized epilepsy with febrile seizures plus, type 2	2022-03-05	criteria provided, single submitter	clinical testing	The c.5347G>A;p.(Ala1783Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 68570; PMID: 30321769; PMID: 26096185; PMID: 17347258; PMID: 22071555; PMID: 19589774) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ion_trans;PKD_channel) - PM1. This variant is not present in population databases (rs121917980- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 68571) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 17347258) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 26096185) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
3billion	RCV000059445	SCV002572827	pathogenic	Severe myoclonic epilepsy in infancy	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068570). A different missense change at the same codon (p.Ala1783Val) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068571). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV002468563	SCV002764868	pathogenic	Developmental and epileptic encephalopathy 6B	2022-01-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490666	SCV002806345	pathogenic	Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2; Developmental and epileptic encephalopathy 6B	2021-07-01	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059445	SCV000090970	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided