Submissions for variant NM_005045.4(RELN):c.5284G>A (p.Val1762Ile)

gnomAD frequency: 0.01040  dbSNP: rs79499902

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118156	SCV000152505	benign	not specified	2016-09-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000118156	SCV000229793	benign	not specified	2015-01-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000118156	SCV000310792	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000304146	SCV000465949	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000118156	SCV000518190	benign	not specified	2015-11-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Athena Diagnostics	RCV000118156	SCV000614869	benign	not specified	2019-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544742	SCV000656311	benign	Norman-Roberts syndrome; Familial temporal lobe epilepsy 7	2024-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498527	SCV002798586	likely benign	Epilepsy, familial temporal lobe, 1; Norman-Roberts syndrome; Familial temporal lobe epilepsy 7	2021-11-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003430672	SCV004155676	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RELN: BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV003430672	SCV005270573	benign	not provided		criteria provided, single submitter	not provided
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000656001	SCV000588277	pathogenic	Childhood epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000118156	SCV001552646	benign	not specified		no assertion criteria provided	clinical testing	The RELN p.Val1762Ile variant was not identified in the literature but was identified in dbSNP (ID: rs79499902), LOVD 3.0 and ClinVar (classified as benign by Prevention Genetics, Genetic Services Laboratory, University of Chicago, GeneDx, EGL Genetic Diagnostics, and Invitae, as likely benign by Athena Diagnostics Inc and Illumina and as pathogenic by Bioinformatics Core, Luxembourg Center for Systems Biomedicine). The variant was identified in control databases in 1463 of 282336 chromosomes (13 homozygous) at a frequency of 0.005182 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 687 of 24876 chromosomes (freq: 0.02762), Ashkenazi Jewish in 116 of 10364 chromosomes (freq: 0.01119), Latino in 138 of 35352 chromosomes (freq: 0.003904), Other in 27 of 7208 chromosomes (freq: 0.003746), European (non-Finnish) in 413 of 128966 chromosomes (freq: 0.003202), South Asian in 78 of 30612 chromosomes (freq: 0.002548), European (Finnish) in 3 of 25064 chromosomes (freq: 0.00012), and East Asian in 1 of 19894 chromosomes (freq: 0.00005). The p.Val1762 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.