Submissions for variant NM_005045.4(RELN):c.3477C>A (p.Asn1159Lys)

gnomAD frequency: 0.00140  dbSNP: rs114684479

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000307965	SCV000331874	likely benign	not specified	2015-09-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000540494	SCV000565486	likely benign	not provided	2021-01-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 14593429, 14515139, 29358611, 32560555)
Genetic Services Laboratory, University of Chicago	RCV000307965	SCV000596763	likely benign	not specified	2015-09-18	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000307965	SCV000614865	benign	not specified	2020-02-11	criteria provided, single submitter	clinical testing
Invitae	RCV001085073	SCV000656285	likely benign	Norman-Roberts syndrome; Familial temporal lobe epilepsy 7	2024-01-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000540494	SCV001155205	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	RELN: BS2
Illumina Laboratory Services, Illumina	RCV001161946	SCV001323867	benign	Norman-Roberts syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003977725	SCV004791204	likely benign	RELN-related condition	2022-11-17	criteria provided, single submitter	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).
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000656002	SCV000588278	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	RCV000540494	SCV001553126	likely benign	not provided		no assertion criteria provided	clinical testing	The RELN p.Asn1159Lys variant was identified in the literature in two sisters affected with autism (Bonora_2013_PMID:14515139). The variant was identified in dbSNP (ID: rs114684479), LOVD 3.0 and ClinVar (classified as likely benign by GeneDx, Invitae, EGL Genetic Diagnostics and Genetic Services Laboratory, University of Chicago, as uncertain significance by Athena Diagnostics Inc and as pathogenic by Bioinformatics Core, Luxembourg Center for Systems Biomedicine). The variant was identified in control databases in 441 of 282460 chromosomes (2 homozygous) at a frequency of 0.001561 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: Ashkenazi Jewish in 41 of 10358 chromosomes (freq: 0.003958), European (non-Finnish) in 286 of 128856 chromosomes (freq: 0.00222), South Asian in 55 of 30614 chromosomes (freq: 0.001797), Other in 12 of 7208 chromosomes (freq: 0.001665), Latino in 34 of 35392 chromosomes (freq: 0.000961), African in 10 of 24966 chromosomes (freq: 0.000401) and European (Finnish) in 3 of 25122 chromosomes (freq: 0.000119), but was not observed in the East Asian population. The p.Asn1159 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.