ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.2005C>T (p.Arg669Cys)

gnomAD frequency: 0.00038  dbSNP: rs200174262
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523022 SCV000618176 uncertain significance not provided 2022-11-23 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000704306 SCV000833250 likely benign Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7 2025-01-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV002420307 SCV002723442 uncertain significance Inborn genetic diseases 2022-07-08 criteria provided, single submitter clinical testing The p.R658C variant (also known as c.1972C>T), located in coding exon 12 of the SCN9A gene, results from a C to T substitution at nucleotide position 1972. The arginine at codon 658 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species, and cysteine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of primary erythermalgia/small fiber neuropathy and paroxysmal extreme pain disorder (PEPD); however, its contribution to the development of congenital insensitivity to pain (CIP) and hereditary sensory autonomic neuropathy type II (HSAN2D) is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004701593 SCV005204674 likely benign not specified 2024-06-18 criteria provided, single submitter clinical testing Variant summary: SCN9A c.1972C>T (p.Arg658Cys) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 247644 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN9A causing Channelopathy-Associated Congenital Insensitivity To Pain, Autosomal Recessive phenotype (0.0011). To our knowledge, no occurrence of c.1972C>T in individuals affected with Channelopathy-Associated Congenital Insensitivity To Pain, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 449780). Based on the evidence outlined above, the variant was classified as likely benign.

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