ClinVar Miner

Submissions for variant NM_005045.4(RELN):c.7909C>T (p.Arg2637Cys)

dbSNP: rs587780438
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000118141 SCV000152485 uncertain significance not provided 2013-04-16 criteria provided, single submitter clinical testing
Invitae RCV000820140 SCV000960837 uncertain significance Norman-Roberts syndrome; Familial temporal lobe epilepsy 7 2022-10-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2637 of the RELN protein (p.Arg2637Cys). 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. 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 RELN protein function. ClinVar contains an entry for this variant (Variation ID: 130113). This missense change has been observed in individual(s) with clinical features of autosomal dominant lateral temporal lobe epilepsy (PMID: 33453592). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003230406 SCV003929387 pathogenic Familial temporal lobe epilepsy 7 2023-04-27 criteria provided, single submitter clinical testing Variant summary: RELN c.7909C>T (p.Arg2637Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251186 control chromosomes (gnomAD). c.7909C>T has been reported in the literature in multiple families individuals affected with Familial Epilepsy (e.g. Bisulli_2021, Fang_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33453592, 34569441). One ClinVar submitter has assessed the variant since 2014: the variant was classified as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

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