Submissions for variant NM_001365536.1(SCN9A):c.2461G>A (p.Val821Met)

gnomAD frequency: 0.00006  dbSNP: rs41268671

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086993	SCV000299168	likely benign	Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7	2025-01-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000384589	SCV000418574	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.
Illumina Laboratory Services, Illumina	RCV000344215	SCV000418576	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	RCV000402179	SCV000418577	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	RCV000285786	SCV000418578	likely benign	Inherited Erythromelalgia	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000498158	SCV000589358	likely benign	not provided	2021-01-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30392441, 32773395)
Baylor Genetics	RCV001332207	SCV001524449	uncertain significance	Generalized epilepsy with febrile seizures plus, type 7	2019-09-11	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002450757	SCV002737441	uncertain significance	Inborn genetic diseases	2021-04-12	criteria provided, single submitter	clinical testing	The p.V810M variant (also known as c.2428G>A), located in coding exon 14 of the SCN9A gene, results from a G to A substitution at nucleotide position 2428. The valine at codon 810 is replaced by methionine, an amino acid with highly similar properties. This variant was detected in an individual with a complex Charcot-Marie-Tooth disease phenotype; however, clinical details were limited (Antoniadi T et al. BMC Med Genet, 2015 Sep;16:84). In addition, this variant was detected in an individual with diffuse neuropathic pain who also had a variant in SCN5A; the phase of the variants were not specified, and in vitro functional studies to examine the clinical significance of SCN9A p.V810M were inconclusive (Adi T et al. Mol Pain Nov;14:1744806918815007). This amino acid position is well conserved in available vertebrate species; however, methionine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of primary erythermalgia/small fiber neuropathy and paroxysmal extreme pain disorder (PEPD); however, its contribution to the development of congenital insensitivity to pain (CIP) and hereditary sensory autonomic neuropathy type II (HSAN2D) is uncertain.
Revvity Omics, Revvity	RCV000498158	SCV003826973	uncertain significance	not provided	2021-01-19	criteria provided, single submitter	clinical testing