ClinVar Miner

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

dbSNP: rs121917980
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Total submissions: 7
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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
Invitae RCV001240035 SCV001412956 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2021-10-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1783 of the SCN1A protein (p.Ala1783Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC 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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 - - 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.
UniProtKB/Swiss-Prot RCV000059445 SCV000090970 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided

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