2-165992255-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong
The NM_001165963.4(SCN1A):c.5020G>A(p.Gly1674Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1674R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001165963.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.5020G>A | p.Gly1674Ser | missense_variant | Exon 29 of 29 | NM_001165963.4 | ENSP00000501589.1 | |||
SCN1A | ENST00000303395.9 | c.5020G>A | p.Gly1674Ser | missense_variant | Exon 28 of 28 | 5 | ENSP00000303540.4 | |||
SCN1A | ENST00000375405.7 | c.4987G>A | p.Gly1663Ser | missense_variant | Exon 26 of 26 | 5 | ENSP00000364554.3 | |||
SCN1A | ENST00000409050.1 | c.4936G>A | p.Gly1646Ser | missense_variant | Exon 26 of 26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1674 of the SCN1A protein (p.Gly1674Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SCN1A-related conditions (PMID: 26311622, 30619928; Invitae). ClinVar contains an entry for this variant (Variation ID: 1024963). 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 SCN1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Reported previously as pathogenic or likely pathogenic variants in patients with generalized epilepsy with febrile seizures plus (GEFS+) who also had a family history of an affected parent (Kong et al., 2019; Jiang et al., 2020); Reported previously as a maternally inherited variant, from an affected mother, in a patient with febrile seizures and hemiconvulsion-hemiplegia syndrome (Saitoh et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S5 of the fourth homologous domain; This variant is associated with the following publications: (PMID: 32276107, 33391346, 30619928, 26311622) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at