Submissions for variant NM_001377.3(DYNC2H1):c.1360+2del

gnomAD frequency: 0.00002  dbSNP: rs780539887

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180552	SCV000233016	pathogenic	not provided	2014-05-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000180552	SCV002571601	pathogenic	not provided	2022-09-08	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)
Invitae	RCV002516822	SCV003285827	pathogenic	Jeune thoracic dystrophy	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 9 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 (rs780539887, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with short-rib polydactyly syndrome (PMID: 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 199053). 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.
PreventionGenetics, part of Exact Sciences	RCV003407669	SCV004110908	likely pathogenic	DYNC2H1-related condition	2023-03-28	criteria provided, single submitter	clinical testing	The DYNC2H1 c.1360+2delT variant is predicted to result in a deletion affecting a canonical splice site. This variant was reported in the compound heterozygous state in an individual with short rib-polydactyly syndrome, type 3 (Table S2, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.0019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-102991766-GT-G). This variant is interpreted as likely pathogenic.
Dan Cohn Lab, University Of California Los Angeles	RCV001291407	SCV000612023	pathogenic	Asphyxiating thoracic dystrophy 3	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291407	SCV001479900	likely pathogenic	Asphyxiating thoracic dystrophy 3		no assertion criteria provided	research