Submissions for variant NM_001365536.1(SCN9A):c.2576T>C (p.Ile859Thr)

dbSNP: rs80356474

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001067998	SCV001233085	pathogenic	Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 848 of the SCN9A protein (p.Ile848Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant primary erythromelalgia (PMID: 14985375, 29911575). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6350). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SCN9A function (PMID: 15385606). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001270748	SCV001451497	pathogenic	SCN9A-related peripheral neuropathies associated with increased pain	2019-03-12	criteria provided, single submitter	clinical testing	The SCN9A c.2543T>C (p.Ile848Thr) variant is a missense variant and has been reported in at least seven studies, in which it is found in a heterozygous state in a total of 10 individuals with inherited erythromelalgia (Yang et al. 2004; Drenth et al. 2005; Drenth et al. 2008; Natkunarajah et al. 2009; Zhang et al. 2014; Namer et al. 2015; McDonnell et al. 2016). The age of onset was reported at three to five years in individuals carrying the p.Ile848Thr variant. In two families, the variant was shown to segregate with disease. The p.Ile848Thr variant was absent from 350 control subjects and is not found in the Genome Aggregation Database, in a region of good sequence coverage, so the variant is presumed to be rare. Functional studies in C-fibers from a patient carrying the p.Ile848Thr variant demonstrated an enhanced early subnormal conduction in the velocity recovery cycles (Namer et al. 2015). In addition, HEK293 cells expressing this variant exhibited altered sodium channel function compared to wild type (Cummins et al. 2004). Based on the collective evidence and application of the ACMG criteria, the p.Ile848Thr variant is classified as pathogenic for SCN9A-related peripheral neuropathies associated with increased pain.
Revvity Omics, Revvity	RCV001781194	SCV002020035	pathogenic	not provided	2021-03-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001781194	SCV002822713	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000006722	SCV000026913	pathogenic	Primary erythromelalgia	2004-09-22	no assertion criteria provided	literature only
GeneReviews	RCV000006722	SCV000040964	not provided	Primary erythromelalgia		no assertion provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001004018	SCV001162079	likely pathogenic	Acute episodes of neuropathic symptoms; Abnormality of pain sensation		no assertion criteria provided	research