Submissions for variant NM_001365536.1(SCN9A):c.3125C>T (p.Thr1042Ile)

gnomAD frequency: 0.00005  dbSNP: rs757989638

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000559422	SCV000649310	uncertain significance	Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7	2023-08-17	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt SCN9A protein function. ClinVar contains an entry for this variant (Variation ID: 471106). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1031 of the SCN9A protein (p.Thr1031Ile). This variant is present in population databases (rs757989638, gnomAD 0.009%). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 27956748).
Illumina Laboratory Services, Illumina	RCV001131850	SCV001291492	uncertain significance	Primary erythromelalgia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001131851	SCV001291493	uncertain significance	Channelopathy-associated congenital insensitivity to pain, autosomal recessive	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001131852	SCV001291494	uncertain significance	Paroxysmal extreme pain disorder	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002324017	SCV002606387	uncertain significance	Inborn genetic diseases	2021-01-13	criteria provided, single submitter	clinical testing	The p.T1031I variant (also known as c.3092C>T), located in coding exon 16 of the SCN9A gene, results from a C to T substitution at nucleotide position 3092. The threonine at codon 1031 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114672	SCV003799719	uncertain significance	not provided	2023-11-29	criteria provided, single submitter	clinical testing	The SCN9A c.3092C>T; p.Thr1031Ile variant (rs757989638) is reported in the literature in an individual affected with autism (Rubinstein 2018), though to our knowledge it has not been reported in individuals with neuropathy. This variant is found on seven chromosomes (7/279778 alleles) in the Genome Aggregation Database. The threonine at codon 1031 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.514). However, given the lack of clinical and functional data, the significance of the p.Thr1031Ile variant is uncertain at this time. References: Rubinstein M et al. Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism. Mol Psychiatry. 2018 Feb;23(2):231-239. PMID: 27956748.