rs138607170
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PP3_StrongPP5_Very_StrongBS2
The NM_001349253.2(SCN11A):c.673C>T(p.Arg225Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,718 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001349253.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN11A | NM_001349253.2 | c.673C>T | p.Arg225Cys | missense_variant | 9/30 | ENST00000302328.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN11A | ENST00000302328.9 | c.673C>T | p.Arg225Cys | missense_variant | 9/30 | 5 | NM_001349253.2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251312Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135830
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461514Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727086
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Familial episodic pain syndrome with predominantly lower limb involvement Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 07, 2013 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 10, 2022 | The c.673C>T (p.R225C) alteration is located in exon 5 (coding exon 5) of the SCN11A gene. This alteration results from a C to T substitution at nucleotide position 673, causing the arginine (R) at amino acid position 225 to be replaced by a cysteine (C). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple families with episodic pain (Zhang, 2013; Leng, 2017; Castoro, 2018). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.R225C alteration enhanced electrical channel activity and induced hyperexcitability of mouse dorsal root ganglion neurons (Zhang, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | SCN11A: PP1:Strong, PM2, PS4:Moderate, PS3:Supporting - |
Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2022 | ClinVar contains an entry for this variant (Variation ID: 69850). For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN11A function (PMID: 24207120). 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 SCN11A protein function. This missense change has been observed in individuals with familial episodic pain syndrome (PMID: 24207120, 28298626, 30046661, 30557356). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs138607170, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 225 of the SCN11A protein (p.Arg225Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at