ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs1049502301
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Total submissions: 6
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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
Invitae 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).
PreventionGenetics, part of Exact Sciences RCV003955418 SCV004786143 likely pathogenic NEK1-related disorder 2023-12-13 criteria provided, single submitter 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; 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.
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

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