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

gnomAD frequency: 0.00026  dbSNP: rs137853027

Total submissions: 23

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 Laboratory Services, 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 Laboratory Services, 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	Fetal growth restriction; Narrow chest; Bowing of the long bones	2015-07-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	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	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 3015 of the DYNC2H1 protein (p.Asp3015Gly). This variant is present in population databases (rs137853027, gnomAD 0.08%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 23339108, 23456818, 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6503). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000006876	SCV001156775	pathogenic	Asphyxiating thoracic dystrophy 3	2023-10-09	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000006876	SCV001425373	likely pathogenic	Asphyxiating thoracic dystrophy 3	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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000224348	SCV001449805	pathogenic	not provided	2015-06-25	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000224348	SCV001832427	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000006876	SCV001985042	pathogenic	Asphyxiating thoracic dystrophy 3	2021-09-02	criteria provided, single submitter	clinical testing	This variant was observed in compound heterozygosity with variant c.10109del
GeneDx	RCV000224348	SCV002013003	pathogenic	not provided	2022-05-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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: 19442771, 30557390, 28492532, 31974414, 31935347, 23456818, 29068549, 23339108, 34426522, 33726816)
Revvity Omics, Revvity	RCV000006876	SCV002021817	pathogenic	Asphyxiating thoracic dystrophy 3	2023-05-26	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV000006876	SCV002576358	pathogenic	Asphyxiating thoracic dystrophy 3		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006876	SCV004040902	pathogenic	Asphyxiating thoracic dystrophy 3	2023-07-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924807	SCV004740275	likely pathogenic	DYNC2H1-related condition	2024-01-18	criteria provided, single submitter	clinical testing	The DYNC2H1 c.9044A>G variant is predicted to result in the amino acid substitution p.Asp3015Gly. This variant has been reported in the compound heterozygous state in multiple individuals with asphyxiating thoracic dystrophy (Dagoneau et al. 2009. PubMed ID: 19442771; Baujat et al. 2013. PubMed ID: 23339108; Schmidts et al. 2013. PubMed ID: 23456818; Zhang et al. 2017. PubMed ID: 29068549; Marchuk et al. 2018. PubMed ID: 30557390; Čechová et al. 2019. PubMed ID: 31935347; Vora et al. 2020. PubMed ID: 31974414). In vitro functional studies using patient fibroblasts reveal abnormal accumulation of anterograde transport proteins in the tips of cilia, suggesting a disruption of retrograde intraflagellar transport (Schmidts et al. 2013. PubMed ID: 23456818). This variant is interpreted as likely pathogenic.
OMIM	RCV000006876	SCV000027072	pathogenic	Asphyxiating thoracic dystrophy 3	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
University of Washington Center for Mendelian Genomics, University of Washington	RCV000386710	SCV001479536	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224348	SCV001797452	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000224348	SCV001809399	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224348	SCV001953493	pathogenic	not provided		no assertion criteria provided	clinical testing