chr2-166002753-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_001165963.4(SCN1A):c.4003G>A(p.Val1335Met) variant causes a missense, splice region 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. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1335V) has been classified as Likely benign.
Frequency
Consequence
NM_001165963.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.4003G>A | p.Val1335Met | missense_variant, splice_region_variant | Exon 24 of 29 | NM_001165963.4 | ENSP00000501589.1 | |||
SCN1A | ENST00000303395.9 | c.4003G>A | p.Val1335Met | missense_variant, splice_region_variant | Exon 23 of 28 | 5 | ENSP00000303540.4 | |||
SCN1A | ENST00000375405.7 | c.3970G>A | p.Val1324Met | missense_variant, splice_region_variant | Exon 21 of 26 | 5 | ENSP00000364554.3 | |||
SCN1A | ENST00000409050.1 | c.3919G>A | p.Val1307Met | missense_variant, splice_region_variant | Exon 21 of 26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Severe myoclonic epilepsy in infancy Pathogenic:1Other:1
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Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1335 of the SCN1A protein (p.Val1335Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 18413471, 18554359; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68535). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Uncertain:1
The c.4003G>A (p.V1335M) alteration is located in exon 21 (coding exon 21) of the SCN1A gene. This alteration results from a G to A substitution at nucleotide position 4003, causing the valine (V) at amino acid position 1335 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in individuals with features consistent with Dravet syndrome, including one de novo occurrence (Sun, 2008; Zucca, 2008; Silvennoinen, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at