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

dbSNP: rs587780438

Total submissions: 3

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820140	SCV000960837	uncertain significance	Norman-Roberts syndrome; Familial temporal lobe epilepsy 7	2024-12-02	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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with seizures (PMID: 33453592, 34569441). ClinVar contains an entry for this variant (Variation ID: 130113). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RELN protein function with a negative predictive value of 80%. 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.
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.