ClinVar Miner

Submissions for variant NM_005045.4(RELN):c.3477C>A (p.Asn1159Lys) (rs114684479)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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; Epilepsy, familial temporal lobe, 7 2020-11-29 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000540494 SCV001155205 likely benign not provided 2021-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
Bioinformatics Core,Luxembourg Center for Systems Biomedicine RCV000656002 SCV000588278 pathogenic Rolandic epilepsy 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.

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