rs779184118
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_001165963.4(SCN1A):c.986G>T(p.Gly329Val) variant causes a missense change. 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. G329A) has been classified as Likely 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.986G>T | p.Gly329Val | missense_variant | 10/29 | ENST00000674923.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.986G>T | p.Gly329Val | missense_variant | 10/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.487+12798C>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2014 | p.Gly329Val (GGT>GTT): c.986 G>T in exon 7 of the SCN1A gene (NM_001165963.1) A variant of unknown significance has been identified in the SCN1A gene. The G329V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G329V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution alters a conserved position predicted to be between transmembrane segments S5 and S6 of the first homologous domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense mutations in nearby residues (R322I, Y325C, C336Y) have been reported in association with myoclonic epilepsy of infancy and Dravet syndrome, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether the G329V variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s). - |
Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 02, 2017 | - - |
Severe myoclonic epilepsy in infancy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at