rs121917954
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_001165963.4(SCN1A):c.4057G>T(p.Val1353Phe) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1353L) has been classified as Pathogenic.
Frequency
Consequence
NM_001165963.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.4057G>T | p.Val1353Phe | missense_variant | 24/29 | ENST00000674923.1 | |
LOC102724058 | NR_110598.1 | n.176-12914C>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.4057G>T | p.Val1353Phe | missense_variant | 24/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.193-12914C>A | intron_variant, non_coding_transcript_variant |
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
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 09, 2018 | This sequence change replaces valine with phenylalanine at codon 1353 of the SCN1A protein (p.Val1353Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant identified in the SCN1A gene is located in the transmembrane spanning D3-S5 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. For these reasons, this variant has been classified as Pathogenic. The observation of one or more missense substitutions at this codon (p.Val1353Leu) in affected individuals suggests that this may be a clinically significant residue (PMID: 11254444, 14672992). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in an individual affected with SCN1A-related disease (Invitae). This variant is not present in population databases (ExAC no frequency). - |
SCN1A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 22, 2023 | The SCN1A c.4057G>T variant is predicted to result in the amino acid substitution p.Val1353Phe. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An alternate nucleotide change affecting the same amino acid (c.4057G>C; p.Val1353Leu) has been reported in individuals with generalized epilepsy (Wallace et al. 2001. PubMed ID: 11254444), and functional studies support its pathogenicity (Berecki et al. 2019. PubMed ID: 30779207; Lossin et al. 2003. PubMed ID: 14672992). The c.4057G>T (p.Val1353Phe) variant is documented in ClinVar as pathogenic by one laboratory, citing evidence of de novo occurrence (https://www.ncbi.nlm.nih.gov/clinvar/variation/577950/). Although we suspect that the c.4057G>T (p.Val1353Phe) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at