ClinVar Miner

Submissions for variant NM_005045.4(RELN):c.1189G>A (p.Glu397Lys)

gnomAD frequency: 0.00001  dbSNP: rs1554402135
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522779 SCV000616992 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing The E397K variant in the RELN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The E397K 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret E397K as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001851480 SCV002120068 uncertain significance Norman-Roberts syndrome; Familial temporal lobe epilepsy 7 2024-04-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 397 of the RELN protein (p.Glu397Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RELN-related conditions. ClinVar contains an entry for this variant (Variation ID: 449166). 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 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.

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