rs121918632
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001165963.4(SCN1A):āc.4495T>Cā(p.Phe1499Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. F1499F) has been classified as Likely benign.
Frequency
Consequence
NM_001165963.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.4495T>C | p.Phe1499Leu | missense_variant | 27/29 | ENST00000674923.1 | |
LOC102724058 | NR_110598.1 | n.176-19514A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.4495T>C | p.Phe1499Leu | missense_variant | 27/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.193-19514A>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000660 AC: 1AN: 151492Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome ? AF: 0.00000660 AC: 1AN: 151492Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 73978
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 07, 2021 | PP1_strong, PP3, PP4, PM1, PM2, PS3, PS4_moderate - |
Migraine, familial hemiplegic, 3 Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 31, 2009 | - - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2022 | This missense change has been observed in individuals with familial hemiplegic migraine (PMID: 19332696, 30498473). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1499 of the SCN1A protein (p.Phe1499Leu). ClinVar contains an entry for this variant (Variation ID: 12902). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. - |
Severe myoclonic epilepsy in infancy 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