rs863223345
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_014191.4(SCN8A):c.4351G>A(p.Gly1451Ser) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1451G) has been classified as Likely benign.
Frequency
Consequence
NM_014191.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.4351G>A | p.Gly1451Ser | missense_variant | 24/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.4351G>A | p.Gly1451Ser | missense_variant | 24/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.4228G>A | p.Gly1410Ser | missense_variant | 23/26 | ||
SCN8A | NM_001369788.1 | c.4228G>A | p.Gly1410Ser | missense_variant | 23/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.4351G>A | p.Gly1451Ser | missense_variant | 24/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.4351G>A | p.Gly1451Ser | missense_variant | 24/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 13 Pathogenic:3Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 19, 2023 | Variant summary: SCN8A c.4351G>A (p.Gly1451Ser) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249572 control chromosomes. c.4351G>A has been reported in the literature as a recurrent de-novo variant in individuals affected with features of SCN8A-related Epileptic Encephalopathy 13 (example, PMID: 25725044, 31026061, 29100083, 27165006). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an apparent loss of channel activity in HEK cell assay in-vitro (PMID: 25725044). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=4; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | The variant has been previously reported as de novo in a similarly affected individual (PMID: 25725044). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:25725044). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96>=0.6, 3CNET: 0.973>=0.75). A missense variant is a common mechanism associated with Developmental and epileptic encephalopathy 13. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 16, 2021 | The c.4351G>A (p.G1451S) alteration is located in exon 24 (coding exon 23) of the SCN8A gene. This alteration results from a G to A substitution at nucleotide position 4351, causing the glycine (G) at amino acid position 1451 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD), the SCN8A c.4351G>A alteration was not observed, with coverage at this position. This alteration has been reported de novo in multiple unrelated patients with epileptic encephalopathy (Blanchard, 2015; Hamdan, 2017; Denis, 2019). The p.G1451 amino acid is conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional analysis demonstrated that the p.G1451S alteration showed decreased current densities (Blanchard, 2015). Using whole-cell patch clamp measurements in HEK293 cells transfected with wildtype or mutated SCN8A cDNA encoding the NaV1.6α subunit, cells expressing wildtype channels exhibited substantial voltage-evoked currents, while current densities in cells expressing the G1451S mutant were about 10-fold smaller than wildtype-transfected cells which was comparable to those in non-transfected cells. The p.G1451S alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 01, 2020 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect SCN8A protein function (PMID: 25725044). This variant has been observed in individual(s) with clinical features of epileptic encephalopathy (PMID: 31026061, 25725044, 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 192318). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 1451 of the SCN8A protein (p.Gly1451Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2023 | Published functional studies demonstrate a damaging effect, showing a 10-fold decrease in current density compared to wildtype, consistent with a loss of function (Blanchard et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This substitution is predicted to be within the transmembrane segment S6 of the third homologous domain; This variant is associated with the following publications: (PMID: 25725044, 31026061, 32090326, 35627257, 35325842, 27165006, 33915942, 31887642, 30615093, 32916281, 32845893, 29100083, 34979445) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 20, 2016 | - - |
Complex neurodevelopmental disorder Other:1
not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at