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

dbSNP: rs137853031

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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