Submissions for variant NM_001365536.1(SCN9A):c.1846G>A (p.Gly616Arg)

gnomAD frequency: 0.00014  dbSNP: rs201338643

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544928	SCV000649283	uncertain significance	Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 616 of the SCN9A protein (p.Gly616Arg). This variant is present in population databases (rs201338643, gnomAD 0.02%). This missense change has been observed in individual(s) with inherited erythromelalgia (PMID: 20478850). ClinVar contains an entry for this variant (Variation ID: 433099). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SCN9A protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SCN9A function (PMID: 20478850). 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.
GeneDx	RCV001557778	SCV001779605	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Reported previously in the heterozygous state in three related individuals with erythromelagia (Choi et al., 2010); 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: 28150151, 20478850, 30416015, 26220970)
Ambry Genetics	RCV002413370	SCV002716445	uncertain significance	Inborn genetic diseases	2021-06-09	criteria provided, single submitter	clinical testing	The p.G616R variant (also known as c.1846G>A), located in coding exon 11 of the SCN9A gene, results from a G to A substitution at nucleotide position 1846. The glycine at codon 616 is replaced by arginine, an amino acid with dissimilar properties. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). However, this variant appears to segregate with erythromelalgia in one family, and experimental studies show that the G616R mutation depolarizes steady-state inactivation within the adult, but not the neonatal transcript isoform of Nav1.7 (Choi JS et al. Brain, 2010 Jun;133:1823-35). This amino acid position is well conserved in available vertebrate species; however, arginine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002475989	SCV002782126	uncertain significance	Primary erythromelalgia; Neuropathy, hereditary sensory and autonomic, type 2A; Paroxysmal extreme pain disorder; Channelopathy-associated congenital insensitivity to pain, autosomal recessive	2021-11-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001557778	SCV005412929	uncertain significance	not provided	2024-08-02	criteria provided, single submitter	clinical testing	PP3_moderate
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005051787	SCV005685530	uncertain significance	SCN9A-related neuropathic pain syndromes	2024-07-11	criteria provided, single submitter	clinical testing	The SCN9A c.1846G>A (p.Gly616Arg) variant has been reported in three related individuals affected with adult-onset primary erythromelalgia (Choi JS et al., PMID: 20478850). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.0171% in the European non-Finnish population. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to SCN9A function. Functional studies show that the variant affects the steady-state inactivation of Nav1.7 in the adult transcript isoform, but not in the neonatal isoform, indicating that this variant impacts protein function (Choi JS et al., PMID: 20478850). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000655988	SCV000588264	pathogenic	Self-limited epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15
GenomeConnect - Invitae Patient Insights Network	RCV001535614	SCV001749635	not provided	Primary erythromelalgia; Neuropathy, hereditary sensory and autonomic, type 2A; Paroxysmal extreme pain disorder; Channelopathy-associated congenital insensitivity to pain, autosomal recessive; Generalized epilepsy with febrile seizures plus		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.