Submissions for variant NM_001365536.1(SCN9A):c.1285C>T (p.Arg429Cys)

gnomAD frequency: 0.00001  dbSNP: rs763256222

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000662199	SCV000784554	uncertain significance	Primary erythromelalgia	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000662200	SCV000784555	uncertain significance	Generalized epilepsy with febrile seizures plus, type 7	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000662201	SCV000784556	uncertain significance	Channelopathy-associated congenital insensitivity to pain, autosomal recessive	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000662202	SCV000784557	uncertain significance	Febrile seizures, familial, 1	2018-03-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001129582	SCV001289119	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000662201	SCV001289120	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	RCV000662199	SCV001294358	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV001855402	SCV002280439	uncertain significance	Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7	2023-04-06	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: 548618). This missense change has been observed in individual(s) with generalized epilepsy with febrile seizures (PMID: 31394368). This variant is present in population databases (rs763256222, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 429 of the SCN9A protein (p.Arg429Cys).
Ambry Genetics	RCV002386134	SCV002691473	uncertain significance	Inborn genetic diseases	2020-01-15	criteria provided, single submitter	clinical testing	The p.R429C variant (also known as c.1285C>T), located in coding exon 9 of the SCN9A gene, results from a C to T substitution at nucleotide position 1285. The arginine at codon 429 is replaced by cysteine, an amino acid with highly dissimilar properties. This nucleotide position is well conserved in available vertebrate species. This amino acid position is not well 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.