ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.6614G>A (p.Arg2205His)

dbSNP: rs137853031
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000515877 SCV000630954 pathogenic Jeune thoracic dystrophy 2023-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2205 of the DYNC2H1 protein (p.Arg2205His). This variant is present in population databases (rs137853031, gnomAD 0.003%). This missense change has been observed in individual(s) with short rib polydactyly syndrome (PMID: 19361615, 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6507). 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. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756059 SCV000883772 likely pathogenic not provided 2017-08-18 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000756059 SCV001832336 pathogenic not provided 2019-11-30 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000006880 SCV004175682 likely pathogenic Asphyxiating thoracic dystrophy 3 2022-10-04 criteria provided, single submitter clinical testing The DYNC2H1 c.6614G>A variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PM3) The DYNC2H1 c.6614G>A variant is a single nucleotide change in exon 41 of 89 of the DYNC2H1 gene, which is predicted to change the amino acid arginine at position 2205 in the protein to histidine. The variant has been reported in at least 2 probands with a clinical presentation of short rib-polydactyly syndrome (PMID:19361615, PMID:29068549) (PS4_Moderate). This variant is absent from population databases (PM2). The phase of this variant with the p.Trp860Ter variant cannot be determined without parental studies. However, this variant was reported to be in trans with a pathogenic variant p.Arg2838Ter for this recessive condition (PMID:19361615) (PM3). Computational predictions provide conflicting interpretations of pathogenicity for this variant (PP3 and BP4 not met). The variant has been reported in dbSNP (rs137853031) and in the HGMD database: CM091950. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 6507).
OMIM RCV000006880 SCV000027076 pathogenic Asphyxiating thoracic dystrophy 3 2009-04-01 no assertion criteria provided literature only
Dan Cohn Lab, University Of California Los Angeles RCV000006880 SCV000611993 pathogenic Asphyxiating thoracic dystrophy 3 2017-06-01 no assertion criteria provided research
Dan Cohn Lab, University Of California Los Angeles RCV000515877 SCV000612017 pathogenic Jeune thoracic dystrophy 2017-06-01 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000006880 SCV001479727 likely pathogenic Asphyxiating thoracic dystrophy 3 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000515877 SCV001479894 likely pathogenic Jeune thoracic dystrophy no assertion criteria provided research

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