Submissions for variant NM_001377.3(DYNC2H1):c.1288C>T (p.Arg430Cys)

gnomAD frequency: 0.00053  dbSNP: rs374073337

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489699	SCV000576879	uncertain significance	not provided	2017-04-17	criteria provided, single submitter	clinical testing	The R430C variant in the DYNC2H1 gene has been reported in a patient with short rib polydactyly syndrome; the variant was maternally inherited and in cis with another variant and in trans with a third paternally inherited variant (El Hokayem et al., 2012). The R430C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R430C variant is a non-conservative amino acid substitution, which occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R430C as a variant of uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000489699	SCV001148395	uncertain significance	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001799668	SCV002044435	uncertain significance	Asphyxiating thoracic dystrophy 3	2021-12-09	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_001080463.2:c.1856A>G._x000D_ Criteria applied: PM3, PM5, PP3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001799668	SCV002048359	uncertain significance	Asphyxiating thoracic dystrophy 3	2021-10-08	criteria provided, single submitter	clinical testing	The DYNC2H1 c.1288C>T; p.Arg430Cys variant (rs374073337) is reported in the literature an individual affected with short rib polydactyly type II in cis with a second variant and in trans with a third pathogenic variant (El Hokayem 2012). In addition, this variant was found in one individual with kidney dysplasia, cerebellar hypoplasia and polydactyly in trans with a pathogenic variant (Liang 2020). This variant is found in the general population with an overall allele frequency of 0.02% (52/248810 alleles) in the Genome Aggregation Database. The arginine at codon 430 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.534). However, given the lack of clinical and functional data, the significance of the p.Arg430Cys variant is uncertain at this time. 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. Liang N et al. 28 novel mutations identified from 33 Chinese patients with cilia-related kidney disorders. Clin Chim Acta. 2020 Feb;501:207-215. PMID: 31730820.
Invitae	RCV001856900	SCV002119708	uncertain significance	Jeune thoracic dystrophy	2022-08-16	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 430 of the DYNC2H1 protein (p.Arg430Cys). This variant is present in population databases (rs374073337, gnomAD 0.03%). This missense change has been observed in individual(s) with short-rib polydactyly syndrome (PMID: 22499340). ClinVar contains an entry for this variant (Variation ID: 426435). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317240	SCV004020776	uncertain significance	not specified	2023-06-13	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.1288C>T (p.Arg430Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 217706 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (0.00022 vs 0.0025), allowing no conclusion about variant significance. c.1288C>T has been reported in the literature in an individual affected with Short-rib polydactyly with another variant in cis and one in trans (El Hokayem_2012), as well as a compound heterozygous individual affected with polycystic kidney dysplasia with polydactyly (Liang_2020). These reports do not provide unequivocal conclusions about association of the variant with Short-rib thoracic dysplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22499340, 31730820, 26489029). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252222	SCV001427973	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing