ClinVar Miner

Submissions for variant NM_005045.4(RELN):c.2722C>A (p.Leu908Ile)

dbSNP: rs767519770
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001055963 SCV001220378 uncertain significance Norman-Roberts syndrome; Familial temporal lobe epilepsy 7 2019-01-17 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RELN-related conditions. This variant is present in population databases (rs767519770, ExAC 0.002%). This sequence change replaces leucine with isoleucine at codon 908 of the RELN protein (p.Leu908Ile). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and isoleucine.
GeneDx RCV001788412 SCV002031199 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
New York Genome Center RCV002227507 SCV002506879 uncertain significance Familial temporal lobe epilepsy 7 2021-06-11 criteria provided, single submitter clinical testing The inherited c.2722C>A, p.Leu908Ile variant identified in the RELN gene has not been reported in the literature in individuals with RELN-related conditions. This variant has one heterozygous allele in gnomAD v3.1.1 suggesting it is not a common benign variant in the populations represented inthis database. In silico algorithms predict a conflicting interpretation of pathogenicity. The p.Leu908 residue is not within a mapped domain of RELN. Given the lack of compelling evidence for its pathogenicity, the inherited c.2722C>A, p.Leu908Ile variant identified in the RELN gene is reported as aVariant of Uncertain Significance.

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