ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.10042+2T>G

gnomAD frequency: 0.00002  dbSNP: rs1261505725
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001857881 SCV002140717 pathogenic Jeune thoracic dystrophy 2023-12-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 66 of the DYNC2H1 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 DYNC2H1 are known to be pathogenic (PMID: 23339108, 32753734, 33755199). This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with short-rib polydactyly syndrome (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446536). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV003159657 SCV003915213 pathogenic not provided 2022-09-22 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29068549, 30773290)
Dan Cohn Lab, University Of California Los Angeles RCV000516017 SCV000611909 pathogenic Short-rib thoracic dysplasia 6 with or without polydactyly 2017-06-01 no assertion criteria provided research
Dan Cohn Lab, University Of California Los Angeles RCV001291173 SCV000611982 pathogenic Asphyxiating thoracic dystrophy 3 2017-06-01 no assertion criteria provided research
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328199 SCV001449317 pathogenic Autosomal recessive polycystic kidney disease 2018-07-06 no assertion criteria provided clinical testing This individual is heterozygous for the c.10063+2T>G variant in the DYNC2H1 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. However, this variant has been submitted as pathogenic on ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/446536/). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.0013% (3 out of 227,450 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) predicts that this variant abolishes the splice donor site. This variant is considered to be pathogenic according to the ACMG guidelines.
University of Washington Center for Mendelian Genomics, University of Washington RCV001291173 SCV001479572 likely pathogenic Asphyxiating thoracic dystrophy 3 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000516017 SCV001479722 likely pathogenic Short-rib thoracic dysplasia 6 with or without polydactyly no assertion criteria provided research

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