rs606231280
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
The NM_001349253.2(SCN11A):c.1142T>C(p.Ile381Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I381F) has been classified as Uncertain significance.
Frequency
Consequence
NM_001349253.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN11A | NM_001349253.2 | c.1142T>C | p.Ile381Thr | missense_variant | 13/30 | ENST00000302328.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN11A | ENST00000302328.9 | c.1142T>C | p.Ile381Thr | missense_variant | 13/30 | 5 | NM_001349253.2 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251210Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135746
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461832Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727222
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hereditary sensory and autonomic neuropathy type 7 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 08, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:24776970, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, PP3_P). A missense variant is a common mechanism associated with Neuropathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Familial episodic pain syndrome with predominantly lower limb involvement Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2014 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 03, 2020 | The p.I381T variant (also known as c.1142T>C), located in coding exon 9 of the SCN11A gene, results from a T to C substitution at nucleotide position 1142. The isoleucine at codon 381 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in two independent patients with painful peripheral neuropathy, one of whom was diagnosed with small fiber neuropathy together with large fiber dysfunction and abnormal nerve conduction studies, and the other with pure small fiber neuropathy and normal nerve conduction studies (Huang J et al. Brain, 2014 Jun;137:1627-42). Functional studies demonstrate that this alteration confers gain of function attributes on the Nav1.9 sodium channel resulting in hyperexcitability of dorsal root ganglion neurons compared to wild-type; however, pathogenic controls were not used for comparison (Huang J et al. Brain, 2014 Jun;137:1627-42). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 17, 2022 | This variant is present in population databases (rs606231280, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 381 of the SCN11A protein (p.Ile381Thr). This missense change has been observed in individuals with SCN11A-related conditions (PMID: 24776970). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SCN11A function (PMID: 24776970). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 157600). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at