Submissions for variant NM_001365536.1(SCN9A):c.2192T>A (p.Ile731Lys)

gnomAD frequency: 0.00019  dbSNP: rs200945460

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118297	SCV000152669	uncertain significance	not specified	2015-04-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000393721	SCV000418600	likely benign	Paroxysmal extreme pain disorder	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000023302	SCV000418602	likely benign	Small fiber neuropathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000191125	SCV000418603	likely benign	Primary erythromelalgia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000311897	SCV000418604	likely benign	Channelopathy-associated congenital insensitivity to pain, autosomal recessive	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476046	SCV000548350	likely benign	Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001546748	SCV001766324	uncertain significance	not provided	2024-04-08	criteria provided, single submitter	clinical testing	Reported in patients with small fiber neuropathy or Charcot-Marie-Tooth type 2, who did not have any other variants identified in the SCN9A gene (PMID: 25250524, 27525141, 26392352); Published functional studies demonstrate that I720K causes a gain of function by altering channel inactivation leading to hyperexcitability of the neurons (PMID: 21698661); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22803682, 27525141, 23280954, 22035805, 26392352, 30672368, 33144682, 25250524, 21698661)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000118297	SCV002511657	uncertain significance	not specified	2022-04-29	criteria provided, single submitter	clinical testing	Variant summary: SCN9A c.2159T>A (p.Ile720Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 212026 control chromosomes. This frequency does not allow conclusions about variant significance. c.2159T>A has been reported in the literature in individuals presenting with features of Small nerve fiber neuropathy (SFN), inherited erythromelalgia (IEM), Charcot-Marie-Tooth disease Type 2 (CMT2), Paroxysomal extreme pain disorder (PEPD) (example, Faber_2012, Goldberg_2012, Antoniadi_2015, Cannon_2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired slow inactivation resulting in neuronal hyperexcitability due to increased number of action potentials resulting from an increase in the number of channels available for activation close to the resting potential of dorsal root ganglion (DRG) neurons (Faber_2012). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mendelics	RCV000118297	SCV002516802	likely benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415425	SCV002724644	uncertain significance	Inborn genetic diseases	2021-11-29	criteria provided, single submitter	clinical testing	The p.I720K variant (also known as c.2159T>A), located in coding exon 13 of the SCN9A gene, results from a T to A substitution at nucleotide position 2159. The isoleucine at codon 720 is replaced by lysine, an amino acid with dissimilar properties. This alteration has been detected in the heterozygous state in multiple patients with adult-onset pain disorders (Cannon A et al. Case Rep Neurol Med, 2016 Jul;2016:9212369; Faber CG et al. Ann. Neurol., 2012 Jan;71:26-39; Goldberg YP et al. Pain, 2012 Jan;153:80-5). Expression of p.I720K in HEK293 cells showed impaired slow inactivation and caused DRG neurons to be hyperexcitable with a 43% reduction in current threshold (Faber CG et al. Ann. Neurol., 2012 Jan;71:26-39). However, given the population frequency of this alteration based on data from the Genome Aggregation Database (gnomAD), it is considered unlikely to cause dominant disease. Its pathogenicity for recessive disease remains unknown. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000191125	SCV002818109	uncertain significance	Primary erythromelalgia	2023-01-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001546748	SCV003826957	uncertain significance	not provided	2021-05-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000311897	SCV003841201	uncertain significance	Channelopathy-associated congenital insensitivity to pain, autosomal recessive		criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000311897	SCV004806514	uncertain significance	Channelopathy-associated congenital insensitivity to pain, autosomal recessive	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000023302	SCV000044593	pathogenic	Small fiber neuropathy	2012-01-01	flagged submission	literature only
Baylor Genetics	RCV000191125	SCV000245533	pathogenic	Primary erythromelalgia	2014-05-02	flagged submission	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory in a 61-year-old female with Bell's palsy, Melkersson-Rosenthal syndrome, right-sided trigeminal neuralgia, fibromyalgia, hyperlipidemia, hyperglycemia, thunderclap headache, similarly affected mother and siblings (not tested). Additionally, this variant has been seen twice in younger individuals without related phenotypes (a 35-year-old female and a 14-year-old male).
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000191125	SCV002583344	uncertain significance	Primary erythromelalgia	2021-12-01	no assertion criteria provided	clinical testing