ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.3002A>G (p.Tyr1001Cys) (rs199692186)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000118298 SCV000152671 uncertain significance not provided 2013-08-27 criteria provided, single submitter clinical testing
GeneDx RCV000118298 SCV000279167 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing The Y990C variant has been reported previously in two individuals with Rolandic epilepsy; however, additional information was not provided (Bobbili et al., 2018). The Y990C variant is observed in 35/6312 (0.6%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The Y990C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
PreventionGenetics,PreventionGenetics RCV000222414 SCV000309310 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000391228 SCV000418517 likely benign Small fiber neuropathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000366834 SCV000418519 benign Primary erythromelalgia 2018-01-12 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 RCV000391236 SCV000418520 uncertain significance Indifference to pain, congenital, autosomal recessive 2018-01-12 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 RCV000313714 SCV000418521 benign Paroxysmal extreme pain disorder 2018-01-12 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.
Invitae RCV001080160 SCV000548364 likely benign Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2020-11-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000118298 SCV000700613 uncertain significance not provided 2016-11-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000118298 SCV001714618 uncertain significance not provided 2020-10-12 criteria provided, single submitter clinical testing
Bioinformatics Core,Luxembourg Center for Systems Biomedicine RCV000655986 SCV000588262 pathogenic Rolandic epilepsy 2017-01-01 no assertion criteria provided case-control CAADphred>15
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000118298 SCV001551045 uncertain significance not provided no assertion criteria provided clinical testing The SCN9A p.Tyr990Cys variant was identified in 3 of 3192 proband chromosomes (frequency: 0.00094; one compound heterozygote and two heterozygotes) from individuals with peripheral neuropathy (Wadhawan_2017_PMID_29264398; Eijkenboom_2018_PMID_30554136). The variant was identified in dbSNP (ID: rs199692186) and ClinVar (classified as likely benign by PreventionGenetics, Invitae and Illumina, and as uncertain significance by GeneDx, EGL Genetic Diagnostics and Genetic Services Laboratory, University of Chicago, and classified as pathogenic by Bioinformatics Core Luxembourg Center for Systems Biomedicine). The variant was identified in control databases in 143 of 236408 chromosomes at a frequency of 0.0006049 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 35 of 6532 chromosomes (freq: 0.005358), Other in 7 of 5826 chromosomes (freq: 0.001202), European (non-Finnish) in 92 of 113582 chromosomes (freq: 0.00081), European (Finnish) in 5 of 22294 chromosomes (freq: 0.000224), African in 3 of 23534 chromosomes (freq: 0.000128) and South Asian in 1 of 20024 chromosomes (freq: 0.00005), but was not observed in the Latino or East Asian populations. The p.Tyr990 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics,Academic Medical Center RCV000118298 SCV001920403 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000118298 SCV001954100 uncertain significance not provided no assertion criteria provided clinical testing

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