rs750516202
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP2PP3_ModerateBS2
The NM_001165963.4(SCN1A):c.1852C>T(p.Arg618Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R618S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001165963.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.1852C>T | p.Arg618Cys | missense_variant | 14/29 | ENST00000674923.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.1852C>T | p.Arg618Cys | missense_variant | 14/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.487+7730G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251358Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135842
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727242
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2023 | Observed in the homozygous state in siblings with febrile seizures and focal seizures, parents were unaffected (Brunklaus et al., 2015); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35813073, 35571373, 35074891, 25795284) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | SCN1A: PM2, PP2 - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 08, 2023 | 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 220200). This missense change has been observed in individuals with generalized epilepsy with febrile seizures plus (PMID: 35571373; Invitae). This variant was reported in the homozygous state in two siblings affected with febrile seizures plus focal seizures and in the heterozygous state in the unaffected carrier parents (PMID: 25795284). Although SCN1A-related epilepsy is typically dominant, the authors propose that this variant may cause a recessive form of the disorder. This variant is present in population databases (rs750516202, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 618 of the SCN1A protein (p.Arg618Cys). - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2022 | The c.1852C>T (p.R618C) alteration is located in exon 11 (coding exon 11) of the SCN1A gene. This alteration results from a C to T substitution at nucleotide position 1852, causing the arginine (R) at amino acid position 618 to be replaced by a cysteine (C). 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