Submissions for variant NM_001377.3(DYNC2H1):c.7594C>T (p.Arg2532Trp)

gnomAD frequency: 0.00004  dbSNP: rs1350329646

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199059	SCV001370054	likely pathogenic	Asphyxiating thoracic dystrophy 3	2019-01-17	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PS1.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001543510	SCV001762124	likely pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001543510	SCV001795813	likely pathogenic	not provided	2023-03-06	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23339108, 23456818, 34426522, 34040173, 35783601, 32752906, 29068549)
MGZ Medical Genetics Center	RCV001199059	SCV002579317	uncertain significance	Asphyxiating thoracic dystrophy 3	2021-06-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001199059	SCV004562440	likely pathogenic	Asphyxiating thoracic dystrophy 3	2023-09-05	criteria provided, single submitter	clinical testing	The DYNC2H1 c.7594C>T; p.Arg2532Trp variant (rs1350329646) is reported as homozygous and compound heterozygous in the literature in multiple individuals affected with asphyxiating thoracic dystrophy and short-rib thoracic dysplasia (Baujat 2013, Doornbos 2021, Jelin 2022, Schmidts 2013). This variant is also reported in ClinVar (Variation ID: 446613) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.196). Based on available information, this variant is considered to be likely pathogenic. References: Baujat G et al. Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. J Med Genet. 2013 Feb;50(2):91-8. PMID: 23339108. Doornbos C et al. Cell-based assay for ciliopathy patients to improve accurate diagnosis using ALPACA. Eur J Hum Genet. 2021 Nov;29(11):1677-1689. PMID: 34040173. Jelin AC et al. Molecular testing strategies in the evaluation of fetal skeletal dysplasia. J Matern Fetal Neonatal Med. 2022 Jul;35(14):2788-2794. PMID: 32752906. 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. PMID: 23456818.
Invitae	RCV000515993	SCV004612389	pathogenic	Jeune thoracic dystrophy	2023-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2532 of the DYNC2H1 protein (p.Arg2532Trp). This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individuals with clinical features of asphyxiating thoracic dysplasia (PMID: 23339108, 23456818, 34040173). ClinVar contains an entry for this variant (Variation ID: 446613). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYNC2H1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Dan Cohn Lab, University Of California Los Angeles	RCV000515993	SCV000612015	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515993	SCV001479892	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001199059	SCV001548283	likely pathogenic	Asphyxiating thoracic dystrophy 3		no assertion criteria provided	research