ClinVar Miner

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

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Total submissions: 9
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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
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
Dan Cohn Lab,University Of California Los Angeles RCV000386710 SCV000611921 pathogenic Jeune thoracic dystrophy 2017-06-01 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224348 SCV000708108 likely pathogenic not provided 2017-06-23 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
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.
OMIM RCV000006876 SCV000027072 pathogenic Short-rib thoracic dysplasia 3 with or without polydactyly 2009-05-01 no assertion criteria provided literature only
Rare Disease Group, Clinical Genetics,Karolinska Institutet RCV000386710 SCV000788360 likely pathogenic Jeune thoracic dystrophy 2018-05-01 criteria provided, single submitter research

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