Submissions for variant NM_001377.3(DYNC2H1):c.7441C>T (p.Arg2481Ter)

gnomAD frequency: 0.00001  dbSNP: rs537704873

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000998	SCV001158104	pathogenic	not specified	2019-01-17	criteria provided, single submitter	clinical testing	The DYNC2H1 c.7441C>T; p.Arg2481Ter variant (rs537704873) has been described in the compound heterozygous state in at least one individual affected with asphyxiating thoracic dystrophy (ATD; Zhang 2018). It contains an entry in ClinVar (Variation ID: 446605), and is observed in the general population at a low overall frequency of 0.002% (5/230370 alleles, 1 homozygote) 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. Additionally, several downstream truncating variants have been described in association with ATD (Dagoneau 2009, Schmidts 2013, Zhang 2018). Based on available information, the p.Arg2481Ter variant is considered pathogenic. REFERENCES Dagoneau N et al. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet. 2009 May;84(5):706-11. Schmidts M et al. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. J Med Genet. 2013 May;50(5):309-23. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166.
Invitae	RCV000515965	SCV004678606	pathogenic	Jeune thoracic dystrophy	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2481*) in the DYNC2H1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYNC2H1 are known to be pathogenic (PMID: 23339108, 32753734, 33755199). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446605). 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.
Dan Cohn Lab, University Of California Los Angeles	RCV000515965	SCV000612006	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515965	SCV001479740	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research