ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.3944T>C (p.Ile1315Thr) (rs202235611)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000276112 SCV000418383 benign Paroxysmal extreme pain disorder 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000375646 SCV000418385 uncertain significance Indifference to pain, congenital, autosomal recessive 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000340680 SCV000418387 uncertain significance Inherited Erythromelalgia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000376885 SCV000418388 benign Primary erythromelalgia 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx RCV000412791 SCV000492430 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN9A gene. The I1304T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I1304T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I1304T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position in transmembrane segment S4 in the 3rd homologous domain at a position that is not conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000647772 SCV000769575 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1304 of the SCN9A protein (p.Ile1304Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs202235611, ExAC 0.02%). This variant has not been reported in the literature in individuals with SCN9A-related disease. ClinVar contains an entry for this variant (Variation ID: 331965). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001973 SCV001159780 uncertain significance not specified 2018-07-03 criteria provided, single submitter clinical testing The SCN9A c.3911T>C; p.Ile1304Thr variant (rs202235611), to our knowledge, is not reported in the medical literature but is reported as a variant of uncertain significance in ClinVar (Variation ID: 331965). This variant is found in the East Asian population with an overall allele frequency of 0.02% (4/18868 alleles) in the Genome Aggregation Database. The isoleucine at codon 1304 is moderately conserved, but occurs as a threonine in several other vertebrates. Computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the SCN9A c.3911T>C; p.Ile1304Thr variant is uncertain at this time.

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