Submissions for variant NM_005045.4(RELN):c.7757C>T (p.Thr2586Ile)

gnomAD frequency: 0.00004  dbSNP: rs202172902

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV000660397	SCV000782478	uncertain significance	Familial temporal lobe epilepsy 7	2016-08-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001163679	SCV001325741	uncertain significance	Norman-Roberts syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001756118	SCV002005735	uncertain significance	not provided	2019-10-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002507146	SCV002815707	uncertain significance	Epilepsy, familial temporal lobe, 1; Norman-Roberts syndrome; Familial temporal lobe epilepsy 7	2022-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002530568	SCV003280089	uncertain significance	Norman-Roberts syndrome; Familial temporal lobe epilepsy 7	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2586 of the RELN protein (p.Thr2586Ile). This variant is present in population databases (rs202172902, gnomAD 0.01%). 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: 547863). 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.
Ambry Genetics	RCV002530567	SCV003716084	uncertain significance	Inborn genetic diseases	2022-11-01	criteria provided, single submitter	clinical testing	The c.7757C>T (p.T2586I) alteration is located in exon 49 (coding exon 49) of the RELN gene. This alteration results from a C to T substitution at nucleotide position 7757, causing the threonine (T) at amino acid position 2586 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.