ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.10573C>T (p.Arg3525Ter) (rs181011657)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532727 SCV000630940 pathogenic Jeune thoracic dystrophy 2017-09-06 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. This variant is present in population databases (rs181011657, ExAC 0.1%). This variant has been reported in an individual affected with short-rib polydactyly type I, Saldino-Noonan type (PMID: 27925158). Loss-of-function variants in DYNC2H1 are known to be pathogenic (PMID: 23339108). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757197 SCV000885335 pathogenic not provided 2018-06-30 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.
Dan Cohn Lab,University Of California Los Angeles RCV000516110 SCV000611959 pathogenic Short-rib polydactyly syndrome type III 2017-06-01 no assertion criteria provided research
Foundation for Research in Genetics and Endocrinology,Institute of Human Genetics RCV000578494 SCV000678271 likely pathogenic Short-rib thoracic dysplasia 3 with or without polydactyly 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.

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