ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.9044A>G (p.Asp3015Gly) (rs137853027)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224348 SCV000281195 pathogenic not provided 2015-03-13 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778103 SCV000366771 pathogenic DYNC2H1-Related Disorders 2018-05-07 criteria provided, single submitter clinical testing The DYNC2H1 c.9044A>G (p.Asp3015Gly) missense variant has been reported in two studies in which it is found in a compound heterozygous state with a null variant in five individuals diagnosed with asphyxiating thoracic dystrophy (ATD), including two from one family. One of the individuals also carried a large deletion in the DYNC2H1 gene (Dagoneau et al. 2009; Schmidts et al. 2013). The p.Asp3015Gly variant was also found in a heterozygous state in three unaffected family members. The variant has not been reported in the literature in association with short-rib polydactyly syndrome which is also associated with variants in the DYNC2H1 gene. The p.Asp3015Gly variant was present at a frequency of < 0.005 in 1210 control chromosomes and is reported at a frequency of 0.000789 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies in patient fibroblasts demonstrated accumulation of transport proteins in the ciliary tips compared to wild type suggesting disrupted retrograde intraflagellar transport in cilia (Schmidts et al. 2013). Based on the collective evidence, the p.Asp3015Gly variant is classified as pathogenic for DYNC2H1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina RCV000292391 SCV000366772 uncertain significance Short Rib Polydactyly Syndrome 2016-06-14 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415231 SCV000492857 pathogenic Narrow chest; Intrauterine growth retardation; Bowing of the long bones 2015-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224348 SCV000708108 likely pathogenic not provided 2017-06-23 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics,Karolinska Institutet RCV000386710 SCV000788360 likely pathogenic Jeune thoracic dystrophy 2018-05-01 criteria provided, single submitter research
Invitae RCV000386710 SCV000814721 pathogenic Jeune thoracic dystrophy 2018-01-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 3015 of the DYNC2H1 protein (p.Asp3015Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs137853027, ExAC 0.05%). This variant has been reported to segregate with asphyxiating thoracic dystrophy in a family (PMID: 19442771), and has been reported in combination with another DYNC2H1 variant in an individuals affected with asphyxiating thoracic dystrophy (PMID: 23339108, 23456818, 29068549). ClinVar contains an entry for this variant (Variation ID: 6503). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000237 SCV001156775 pathogenic not specified 2019-01-17 criteria provided, single submitter clinical testing The DYNC2H1 c.9044A>G; p.Asp3015Gly variant (rs137853027) has been described in the compound heterozygous state in several individuals affected with asphyxiating thoracic dystrophy (ATD; Baujat 2013, Dagoneau 2009, Schmidts 2013, Zhang 2018). It contains an entry in ClinVar (Variation ID: 6503), and is observed in the general population at an overall frequency of 0.026% (73/279976 alleles) in the Genome Aggregation Database. The aspartic acid at codon 3015 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Functional studies using fibroblasts from patients who harbor this variant demonstrate abnormal accumulation of anterograde transport proteins in the tips of cilia and disrupted intraflagellar transport (Schmidts 2013). Based on available information, this variant is considered 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. 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198341 SCV001369240 pathogenic Narrow chest; Intrauterine growth retardation; Short long bone; Bowing of the long bones 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. This variant was detected in heterozygous state.
Johns Hopkins Genomics,Johns Hopkins University RCV000006876 SCV001425373 likely pathogenic Short-rib thoracic dysplasia 3 with or without polydactyly 2020-05-19 criteria provided, single submitter clinical testing This DYNC2H1 variant (rs137853027) is rare (<0.1%) in a large population dataset (gnomAD: 73/279976 total alleles; 0.026%; no homozygotes). It has been reported previously in patients with Short-rib thoracic dysplasia (SRTD) and has an entry in ClinVar. Three bioinformatic tools queried predict that p.Asp3051Gly would be damaging, and the asparatic acid residue at this position is strongly conserved across all species assessed. Bioinformatic analysis predicts that this variant would not affect normal exon 57 splicing, although this has not been confirmed experimentally to our knowledge. In addition, functional studies using patient fibroblasts containing this variant show abnormal accumulation of transport proteins in the tips of cilia, suggesting a disruption of retrograde intraflagellar transport. We consider this variant to be likely pathogenic.
OMIM RCV000006876 SCV000027072 pathogenic Short-rib thoracic dysplasia 3 with or without polydactyly 2009-05-01 no assertion criteria provided literature only
Dan Cohn Lab,University Of California Los Angeles RCV000386710 SCV000611921 pathogenic Jeune thoracic dystrophy 2017-06-01 no assertion criteria provided research

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