Submissions for variant NM_001377.3(DYNC2H1):c.988C>T (p.Arg330Cys)

gnomAD frequency: 0.00001  dbSNP: rs397514637

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000515863	SCV000828501	pathogenic	Jeune thoracic dystrophy	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 330 of the DYNC2H1 protein (p.Arg330Cys). This variant is present in population databases (rs397514637, gnomAD 0.01%). This missense change has been observed in individual(s) with short-rib polydactyly syndrome, type II (SRPSII), SRPS type III, and ATD and asphyxiating thoracic dystrophy (ATD) (PMID: 22499340, 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: 40070). 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%. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000033160	SCV002048711	likely pathogenic	Asphyxiating thoracic dystrophy 3	2021-09-13	criteria provided, single submitter	clinical testing	The DYNC2H1 c.988C>T; p.Arg330Cys variant (rs397514637) is reported in the homozygous or compound heterozygous state in individuals with short-rib polydactyly and Jeune asphyxiating thoracic dystrophy (El Hokayem 2012, Schmidts 2013, Zhang 2018). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 40070) and is listed in the general population with an overall allele frequency of 0.003% (8/246,812 alleles) in the Genome Aggregation Database. The arginine at codon 330 is highly conserved and occurs in the N-terminal tail domain, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.641). Based on available information, this variant is considered to be likely pathogenic. References: El Hokayem J et al. NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases. J Med Genet. 2012 Apr;49(4):227-33. PMID: 22499340. 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. PMID: 23456818. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549.
OMIM	RCV000033160	SCV000056942	pathogenic	Asphyxiating thoracic dystrophy 3	2012-04-01	no assertion criteria provided	literature only
Dan Cohn Lab, University Of California Los Angeles	RCV000515863	SCV000611911	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
Dan Cohn Lab, University Of California Los Angeles	RCV000033160	SCV000611944	pathogenic	Asphyxiating thoracic dystrophy 3	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000033160	SCV001479749	likely pathogenic	Asphyxiating thoracic dystrophy 3		no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515863	SCV001479868	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research