Submissions for variant NM_001377.3(DYNC2H1):c.10573C>T (p.Arg3525Ter)

gnomAD frequency: 0.00014  dbSNP: rs181011657

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000532727	SCV000630940	pathogenic	Jeune thoracic dystrophy	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3532*) 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). This variant is present in population databases (rs181011657, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with short-rib polydactyly type I, Saldino-Noonan type (PMID: 27925158). ClinVar contains an entry for this variant (Variation ID: 446570). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000578494	SCV000885335	pathogenic	Asphyxiating thoracic dystrophy 3	2021-09-13	criteria provided, single submitter	clinical testing	The DYNC2H1 c.10594C>T; p.Arg3532Ter variant (rs181011657) is reported in the literature in the compound heterozygous state, in individuals with short-rib polydactyly (Badiner 2017, Vora 2017), and bilateral hand and foot polydactyly (Meng 2017). This variant is in ClinVar (Variation ID: 446570) and is listed in the genome Aggregation Database with an overall population frequency of 0.006% (identified on 17 out of 264,854 chromosomes). The c.10594C>T variant creates a termination in the DYNC2H1 protein at codon 3532 in exon 70 which is predicted to result in a truncated or absent protein product. Based on these observations, the p.Arg3532Ter has been classified as pathogenic. Pathogenic variants in DYNC2H1 follow autosomal recessive and digenic recessive (with NEK1 variants) inheritance patterns and are associated with short-rib thoracic dysplasia (SRTD) 3 with or without polydactyly (MIM: 613091). REFERENCES Badiner N et al. Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino-Noonan type. Clin Genet. 2017 Aug;92(2):158-165. Meng L et al. Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management. JAMA Pediatr. 2017 Dec 4;171(12):e173438. Vora NL et al. Prenatal exome sequencing in anomalous fetuses: new opportunities and challenges. Genet Med. 2017 Nov;19(11):1207-1216.
GeneDx	RCV002473030	SCV002770390	pathogenic	not provided	2023-02-27	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 31589614, 31345219, 34426522, 31974414, 28973083, 29068549, 28518170, 27925158)
Dan Cohn Lab, University Of California Los Angeles	RCV000578494	SCV000611959	pathogenic	Asphyxiating thoracic dystrophy 3	2017-06-01	no assertion criteria provided	research
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000578494	SCV000678271	likely pathogenic	Asphyxiating thoracic dystrophy 3	2018-01-03	no assertion criteria provided	clinical testing	The observed variant c.10594C>T (p.R3532X) has a minor allele frequency of 0.02% in The 1000 Genomes and 0.01% in ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2.
University of Washington Center for Mendelian Genomics, University of Washington	RCV000578494	SCV001479569	likely pathogenic	Asphyxiating thoracic dystrophy 3		no assertion criteria provided	research