ClinVar Miner

Submissions for variant NM_005045.4(RELN):c.416C>T (p.Thr139Ile)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003059640 SCV003354161 uncertain significance Norman-Roberts syndrome; Familial temporal lobe epilepsy 7 2022-05-08 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RELN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 139 of the RELN protein (p.Thr139Ile).
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center RCV004784088 SCV005397185 uncertain significance Norman-Roberts syndrome 2022-12-27 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (C>T) at coding position 416 of the RELN gene that results in a threonine to isoleucine amino acid change at residue 139 of the RELN protein product, Reelin. This is a novel variant that has not been reported to databases of clinically annotated variants, or observed in the literature in individuals with RELN-related illness, to our knowledge. This variant is also not observed in the gnomAD population database (0 of ~250,000 alleles). Multiple bioinformatic tools predict that this variant would be damaging, and the Thr139 residue is well conserved across the vertebrate species examined. Functiol studies testing the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: PM2, PP3

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