Submissions for variant NM_005045.4(RELN):c.6520G>A (p.Glu2174Lys)

gnomAD frequency: 0.00043  dbSNP: rs146877597

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724003	SCV000230593	uncertain significance	not provided	2016-09-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000377790	SCV000465936	uncertain significance	Norman-Roberts syndrome	2018-01-12	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	RCV000724003	SCV000565487	uncertain significance	not provided	2016-02-11	criteria provided, single submitter	clinical testing	p.Glu2174Lys (GAA>AAA): c.6520 G>A in exon 42 of the RELN gene (NM_005045.3) A variant of unknown significance has been identified in the RELN gene. The E2174K variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The E2174K 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, other missense variants have not been reported in this region of the protein (Stenson et al., 2009). Therefore, based on the currently available information, it is unclear whether the E2174K variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526248	SCV000656338	benign	Norman-Roberts syndrome; Familial temporal lobe epilepsy 7	2023-12-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765906	SCV000897326	uncertain significance	Epilepsy, familial temporal lobe, 1; Norman-Roberts syndrome; Familial temporal lobe epilepsy 7	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000377790	SCV001440340	uncertain significance	Norman-Roberts syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002516775	SCV003599688	uncertain significance	Inborn genetic diseases	2021-09-28	criteria provided, single submitter	clinical testing	Unlikely to be causative of RELN-related lateral temporal epilepsy (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004739564	SCV005350333	likely benign	RELN-related disorder	2024-06-18	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).