ClinVar Miner

Submissions for variant NM_018706.5(DHTKD1):c.2185G>A (rs117225135)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000238689 SCV000603318 uncertain significance not provided 2018-01-22 criteria provided, single submitter clinical testing The p.Gly729Arg has been previously reported in association with 2-aminoadipic 2-oxoadipic aciduria in multiple unrelated individuals in the compound heterozygous state along with loss of function variants of DHTKD1 (Danhauser 2012 and Hagen 2015). Functional studies performed by Danhauser et al. in fibroblasts isolated from carriers of the p.Gly729Arg variant demonstrated defective lysine metabolism which was corrected by the addition of wild type DHTKD1. This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.3% (identified on 347 out of 125,736 chromosomes), and is listed in ClinVar as likely pathogenic/uncertain significance (ID 39564). Based on the available information, the clinical significance of the p.Gly729Arg variant in relation to CMT disease cannot be determined with certainty, although it is likely to be pathogenic in relation to 2-aminoadipic 2-oxoadipic aciduria.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238689 SCV000297287 likely pathogenic not provided 2015-07-27 criteria provided, single submitter clinical testing
GeneDx RCV000238689 SCV000617853 uncertain significance not provided 2017-07-24 criteria provided, single submitter clinical testing The G729R variant in the DHTKD1 gene has been reported previously in multiple unrelated individuals with biochemical features of alpha-aminoadipic and alpha-ketoadipic aciduria who also harbored an additional variant in the DHTKD1 gene (Danhauser et al., 2012; Hagen et al., 2015; Stiles et al., 2016). Some of these individuals also had variable neurological features such as developmental delays and seizures. However, not all individuals were screened for variants in other neurodevelopmental genes, and some harbored additional genetic diagnoses that explained the neurological features (Danhauser et al., 2012; Hagnen et al., 2015). The G729R variant is observed in 151/66,498 (0.23%) alleles from individuals of non-Finnish European background, with no homozygous individuals reported, in the ExAC dataset (Lek et al., 2016). The G729R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although this substitution occurs at a position that is not conserved, in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G729R as a variant of uncertain significance.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000791040 SCV000930308 likely pathogenic not specified 2019-04-27 criteria provided, single submitter clinical testing
Institute of Human Genetics,Cologne University RCV000032764 SCV000787771 pathogenic 2-aminoadipic 2-oxoadipic aciduria 2018-04-25 no assertion criteria provided clinical testing
Invitae RCV000032764 SCV000644177 pathogenic 2-aminoadipic 2-oxoadipic aciduria 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 729 of the DHTKD1 protein (p.Gly729Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs117225135, ExAC 0.2%). This variant has been observed in combination with rare missense and loss-of-function variants in individuals affected with 2-aminoadipic 2-oxoadipic aciduria (PMID: 23141293, 25860818, 26141459). Furthermore, it has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with DHTKD1-related disease (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 39564). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000032764 SCV000056528 pathogenic 2-aminoadipic 2-oxoadipic aciduria 2012-12-07 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000032764 SCV000787452 likely pathogenic 2-aminoadipic 2-oxoadipic aciduria 2018-04-16 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for 2-aminoadipic 2-oxoadipic aciduria, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity. PM3-Supporting => PM3 downgraded in strength to Supporting. PS3-Moderate => PS3 downgraded in strength to Moderate.

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