Submissions for variant NM_001199397.3(NEK1):c.3107C>G (p.Ser1036Ter)

gnomAD frequency: 0.00009  dbSNP: rs199947197

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190609	SCV000245643	likely pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly	2014-12-24	criteria provided, single submitter	clinical testing	The p.Ser1036X variant in NEK1 has not been previously reported in the literature, but other variants leading to loss of function of the NEK1 protein have been reported in individuals with autosomal recessive short-rib polydactyly syndrome (Thiel 2011, Hokayem 2012). This variant has been identified in 0.04% (3/8196) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs199947197). Other predicted loss of function variants in NEK1 gene are also rare in the general population, consistent with a pathogenic role. This nonsense variant leads to a premature termination codon at position 1036, which is predicted to lead to a truncated or absent protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Ser1036X variant is likely pathogenic for short-rib polydactyly syndrome in an autosomal recessive manner based on the predicted impact on protein function.
Eurofins Ntd Llc (ga)	RCV000519626	SCV000334723	pathogenic	not provided	2015-09-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000519626	SCV000618452	pathogenic	not provided	2025-02-11	criteria provided, single submitter	clinical testing	Reported using alternate nomenclature p.(S1036X) as a risk allele for familial ALS but further research is needed to understand this association (PMID: 26945885); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as c.3107C>G p.(S1036*); This variant is associated with the following publications: (PMID: 32920598, 28935222, 29068549, 34582081, 32409511, 35896380, 26945885, 37159497, 38849340, 37849306, 39222049, 28123176)
Fulgent Genetics, Fulgent Genetics	RCV000763117	SCV000893661	pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly; Amyotrophic lateral sclerosis, susceptibility to, 24	2018-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000519626	SCV001472491	pathogenic	not provided	2019-12-19	criteria provided, single submitter	clinical testing	The NEK1 c.3023C>G; p.Ser1008Ter variant (rs199947197), also known as c.3107C>G; p.Ser1036Ter for NM_001199397.1, is reported in the literature in the compound heterozygous state with other pathogenic NEK1 variants in individuals affected with short rib-polydactyly syndrome II or axial spondylometaphyseal dysplasia (Wang 2017, Zhang 2018). This variant is reported in ClinVar (Variation ID: 208600), and is found in the general population with an overall allele frequency of 0.012% (33/280416 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Wang Z et al. Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations. J Hum Genet. 2017 Apr;62(4):503-506. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166.
CeGaT Center for Human Genetics Tuebingen	RCV000519626	SCV001748104	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000190609	SCV002018291	pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly	2020-12-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000190609	SCV002240875	pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1008*) in the NEK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEK1 are known to be pathogenic (PMID: 22499340, 29068549). This variant is present in population databases (rs199947197, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of short rib-polydactyly syndrome and/or amyotrophic lateral sclerosis (PMID: 26945885, 28123176, 28935222, 29068549). This variant is also known as c.3107C>G (p.S1036*). ClinVar contains an entry for this variant (Variation ID: 208600). For these reasons, this variant has been classified as Pathogenic.
Dan Cohn Lab, University Of California Los Angeles	RCV000190609	SCV000612093	pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly	2017-06-01	no assertion criteria provided	research
OMIM	RCV000585742	SCV000693684	risk factor	Amyotrophic lateral sclerosis, susceptibility to, 24	2018-02-28	no assertion criteria provided	literature only
OMIM	RCV000190609	SCV000778520	pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly	2018-06-18	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000190609	SCV001479621	likely pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003947589	SCV004760647	likely pathogenic	NEK1-related disorder	2024-09-16	no assertion criteria provided	clinical testing	The NEK1 c.3023C>G variant is predicted to result in premature protein termination (p.Ser1008*). This variant, also described as c.3107C>G (p.Ser1036*), has been reported in the compound heterozygous state in individuals with axial spondylometaphyseal dysplasia and short rib dysplasia (Wang et al. 2017. PubMed ID: 28123176; table S2, Zhang et al. 2017. PubMed ID: 29068549). This variant has also been reported in two brothers with amyotrophic lateral sclerosis (ALS) as well as in an unrelated control; however, the brothers also carried an expanded C9orf72 allele that is likely the most penetrant variant (Nguyen et al. 2017. PubMed ID: 28935222). Additionally, this variant was present in an affected brother and an unaffected brother indicating this variant exhibits incomplete penetrance, which is commonly observed in NEK1 protein-truncating variants (Brenner et al. 2016. PubMed ID: 26945885). This variant has been interpreted as pathogenic and likely pathogenic in ClinVar. Internally, we have reported this variant in multiple individuals undergoing ALS testing as well as finding this variant in the compound heterozygous state in an individual with phenotypic features consistent with short-rib polydactyly. Taken together, we classify this variant as likely pathogenic.