ClinVar Genomic variation as it relates to human health

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.

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.

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)

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.

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.

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.

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).