Submissions for variant NM_005045.4(RELN):c.8490-3T>C

gnomAD frequency: 0.00001  dbSNP: rs373564931

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539081	SCV000656365	uncertain significance	Norman-Roberts syndrome; Familial temporal lobe epilepsy 7	2024-07-19	criteria provided, single submitter	clinical testing	This sequence change falls in intron 52 of the RELN gene. It does not directly change the encoded amino acid sequence of the RELN protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs373564931, gnomAD 0.006%). 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: 475992). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
GeneDx	RCV001764627	SCV002008937	uncertain significance	not provided	2020-01-20	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Revvity Omics, Revvity	RCV003133354	SCV003813834	uncertain significance	Norman-Roberts syndrome	2021-05-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530573	SCV004726614	likely benign	RELN-related disorder	2019-06-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).