Submissions for variant NM_001199397.3(NEK1):c.214+1G>A

gnomAD frequency: 0.00002  dbSNP: rs1049502301

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000492619	SCV000323220	other	Motor neuron disease	2016-08-31	criteria provided, single submitter	case-control	Loss-of-function but lacking segregation data
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278254	SCV002566932	pathogenic	Connective tissue disorder	2022-06-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000515986	SCV003509340	pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly	2022-09-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 266055). Disruption of this splice site has been observed in individual(s) with clinical features of amyotrophic lateral sclerosis and/or short-rib polydactyly syndrome (PMID: 28089114, 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change affects a donor splice site in intron 3 of the NEK1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEK1 are known to be pathogenic (PMID: 22499340, 29068549).
Dan Cohn Lab, University Of California Los Angeles	RCV000515986	SCV000612101	pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515986	SCV001479760	likely pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003955418	SCV004786143	likely pathogenic	NEK1-related disorder	2023-12-13	no assertion criteria provided	clinical testing	The NEK1 c.214+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the heterozygous state in an individual with amyotrophic lateral sclerosis (ALS, Supplementary Table 4, Black et al. 2016. PubMed ID: 28089114). It was also reported in the compound heterozygous state with another protein-truncating variant (p.Ser1036Ter) in two individuals with short-rib polydactyly syndrome II (SRPS; Supplementary Table 2, Zhang et al. 2017. PubMed ID: 29068549). However, regarding the autosomal dominant ALS phenotype, incomplete penetrance and variable expressivity have been described, with at least one study suggesting that the penetrance of NEK1 loss-of-function variants is not high, as loss-of-function variants in this gene have been identified in healthy cohorts (Tsai et al. 2020. PubMed ID: 32462798; http://gnomad.broadinstitute.org/). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in NEK1 are expected to be pathogenic.  This variant is interpreted as likely pathogenic.