ClinVar Miner

Submissions for variant NM_002977.3(SCN9A):c.684C>G (p.Ile228Met) (rs71428908)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000179414 SCV000886082 uncertain significance not provided 2017-11-09 criteria provided, single submitter clinical testing The p.Ile228Met variant (rs71428908) has been reported in association with at least four disease phenotypes, including Dravet syndrome, Charcot-Marie-Tooth type II, Erythermalgia, and small fiber neuropathy (Singh, 2009; Ylikallio, 2014; Namer, 2015; Faber, 2012). These studies do not demonstrate segregation of the variant with disease; however Estacion (2011) demonstrate hyperexcitability of dorsal root ganglia neurons that express the variant. In addition, Persson (2013) showed a 20 percent reduction in neurite length by expression the variant protein in cell culture. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.16 percent in the European Non-Finnish population (identified on 205 out of 126,370 chromosomes), and has been reported to the ClinVar database (Variation ID: 198153). The isoleucine at position 228 is highly conserved up to platypus considering 12 species (Alamut v2.10) and computational analyses of the p.Ile228Met variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Considering the overabundance of this variant in the general population, it is likely a polymorphism, however any role in disease can not be ruled out. Altogether, there is not enough evidence to classify the p.Ile228Met variant with certainty.
Athena Diagnostics Inc RCV000179414 SCV000843758 uncertain significance not provided 2018-01-24 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000179414 SCV000493392 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000179414 SCV000609932 uncertain significance not provided 2017-04-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000179414 SCV000231660 uncertain significance not provided 2017-12-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515449 SCV000611521 uncertain significance Primary erythromelalgia; Hereditary sensory and autonomic neuropathy type IIA; Paroxysmal extreme pain disorder; Severe myoclonic epilepsy in infancy; Indifference to pain, congenital, autosomal recessive; Generalized epilepsy with febrile seizures plus, type 7 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000179414 SCV000292684 likely pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing The I228M variant was initially reported as a modifier for Dravet syndrome when observed in the heterozygous state along with a heterozygous pathogenic variant in a gene known to cause epilepsy, SCN1A; however, I228M was also identified in unaffected controls (Singh et al., 2009). I228M has since been reported in the heterozygous state in multiple individuals with small fiber neuropathy with variable phenotypic expression (Estacion et al., 2011; Faber et al., 2012). Functional studies demonstrate that the I228M variant exhibits a gain-of-function effect which alters the channel function (Estacion et al., 2011; Faber et al., 2012). Additional in vitro studies show that I228M impairs the regeneration and/or degeneration of dorsal root ganglion neuron axons (Persson et al., 2013). It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the I228M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Genetic Services Laboratory, University of Chicago RCV000192901 SCV000248831 uncertain significance not specified 2014-10-31 criteria provided, single submitter clinical testing
Invitae RCV000540917 SCV000649386 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 228 of the SCN9A protein (p.Ile228Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs71428908, ExAC 0.2%). This variant has been reported in an individual affected with Dravet syndrome who also carried a pathogenic variant in SCN1A (PMID: 19763161), and a family affected with axonal neuropathy that also carried a variant in HSPB1 (PMID: 26675522). It has also been reported in individuals affected with small fiber neuropathy with variable clinical presentation (PMID: 22136189), and individuals affected with erythromylalgia (PMID: 25993546, 29911575), and unaffected  individuals (PMID: 19763161). ClinVar contains an entry for this variant (Variation ID: 198153). Experimental studies have shown that this missense change impairs slow inactivation of the channel in vitro (PMID: 22136189, 23280954) and a zebrafish model shows an increase in activity (PMID: 30316835). In summary, this variant is a rare missense change that has been shown to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.