Submissions for variant NM_018706.7(DHTKD1):c.2185G>A (p.Gly729Arg)

gnomAD frequency: 0.00190  dbSNP: rs117225135

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238689	SCV000297287	likely pathogenic	not provided	2015-07-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000238689	SCV000603318	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000238689	SCV000617853	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	Observed in multiple patients in published literature with 2-aminoadipic and 2-oxoadipic aciduria and phenotypes suspected to be related; however, some of these patients harbored other potential explanations for their clinical phenotypes or harbored only one variant in DHTKD1 (Danhauser et al., 2012; Hagen et al., 2015; Stiles et al., 2016); Published functional studies suggest a damaging effect on the function of the 2-oxoadipate dehydrogenase complex (Zhang et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23141293, 26141459, 32303640, 25860818, 30842647, 34426522, 33946784, 35052424)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000032764	SCV000644177	pathogenic	2-aminoadipic 2-oxoadipic aciduria	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 729 of the DHTKD1 protein (p.Gly729Arg). This variant is present in population databases (rs117225135, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with 2-aminoadipic 2-oxoadipic aciduria (PMID: 23141293, 25860818, 26141459; Invitae). 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: 39564). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.
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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000791040	SCV000930308	likely pathogenic	not specified	2019-04-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000032764	SCV001522987	pathogenic	2-aminoadipic 2-oxoadipic aciduria		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000238689	SCV001713526	likely pathogenic	not provided	2022-10-26	criteria provided, single submitter	clinical testing	BP4, PM3, PS3, PS4_moderate
Revvity Omics, Revvity	RCV000238689	SCV002024085	likely pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000032764	SCV002034773	likely pathogenic	2-aminoadipic 2-oxoadipic aciduria	2021-08-20	criteria provided, single submitter	clinical testing	The DHTKD1 c.2185G>A (p.Gly729Arg) variant is a missense variant that has been reported in a total of seven individuals with alpha-aminoadipic and alpha-ketoadipic aciduria, including in a compound heterozygous state in six, including in one where the variant arose de novo, and in a heterozygous state without a second identified allele in one (Danhauser et al. 2012; Hagen et al. 2015; Stiles et al. 2016). One of the individuals who was compound heterozygous presented only with elevated metabolites and biotinidase deficiency; all others presented with more severe phenotypes that included features such as developmental delay, speech delay, intellectual disability, microcephaly, and seizures. Control data are unavailable for this variant, which is reported in the Genome Aggregation Database at a frequency of 0.002748 in the European (non-Finnish) population (version 2.1.1) and was identified in one individual in a homozygous state (version 3.1.1). The higher than expected allele frequency and the homozygous individual may be consistent with variable disease expressivity. In vitro analysis in fibroblasts from patients reported by Danhauser et al. (2012) showed elevated levels of 2-oxoadipate in cells and media when compared to wildtype control fibroblasts, and expression of wildtype DHTKD1 in patient fibroblasts rescued the phenotype and decreased the 2-oxoadipate concentrations to levels consistent with control fibroblasts. Zhang et al. (2020) demonstrated that the p.Gly729Arg variant causes a 50-fold decrease in catalytic efficiency for NADH production when assembled into the 2-oxoadipate dehydrogenase complex (OADHc) in vitro, and impacts the assembly of 2-oxoadipate dehydrogenase with dihydrolipoamide succinyl-transferase, leading to impaired channeling of OADHc intermediates. Bezerra et al. (2020) found that the p.Gly729Arg variant does not impact protein thermostability or overall protein stability. Based on the evidence, the p.Gly729Arg variant is classified as likely pathogenic for alpha-aminoadipic and alpha-ketoadipic aciduria.
Mendelics	RCV000791040	SCV002519094	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000032764	SCV002555875	pathogenic	2-aminoadipic 2-oxoadipic aciduria	2024-05-08	criteria provided, single submitter	clinical testing	Variant summary: DHTKD1 c.2185G>A (p.Gly729Arg) results in a non-conservative amino acid change located in the Transketolase-like, pyrimidine-binding domain (IPR005475) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 248268 control chromosomes. c.2185G>A has been reported in the literature in individuals affected with 2-Aminoadipic 2-Oxoadipic Aciduria (examples: Danhauser_2012, Lee_2014, Hagen_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that this variant impacts normal protein function (Zhang_2020). The following publications have been ascertained in the context of this evaluation (PMID: 23141293, 25860818, 25326637, 32303640). ClinVar contains an entry for this variant (Variation ID: 39564). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002513307	SCV003683539	likely pathogenic	Inborn genetic diseases	2022-06-28	criteria provided, single submitter	clinical testing	The c.2185G>A (p.G729R) alteration is located in exon 13 (coding exon 13) of the DHTKD1 gene. This alteration results from a G to A substitution at nucleotide position 2185, causing the glycine (G) at amino acid position 729 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.17% (465/279662) total alleles studied. The highest observed frequency was 0.27% (352/128094) of European (non-Finnish) alleles. This variant has been detected in the compound heterozygous state with other DHTKD1 variants in multiple unrelated individuals with alpha-aminoadipic and alpha-ketoadipic aciduria (Danhauser, 2012; Hagen, 2015; Stiles, 2016). This amino acid position is well conserved in available vertebrate species. Experimental studies showed this variant has a damaging effect on protein function (Danhauser, 2012; Zhang, 2020). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000238689	SCV004126448	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	DHTKD1: PS3:Supporting, BS1:Supporting
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000032764	SCV004177074	likely pathogenic	2-aminoadipic 2-oxoadipic aciduria	2023-10-02	criteria provided, single submitter	clinical testing	The DHTKD1 c.2185G>A (p.Gly729Arg) variant has been reported in seven individuals affected with alpha-aminoadipic and alpha ketoadipic aciduria (Danhauser K et al., PMID: 23141293; Duran M et al., PMID: 6434826; Hagen J et al., PMID: 25860818; Stiles AR et al., PMID: 26141459). Of those individuals, four were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all confirmed in trans (Danhauser K et al., PMID: 23141293; Duran M et al., PMID: 6434826; Hagen J et al., PMID: 25860818). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.3% in European non-Finnish population. Although in vitro analysis indicates that the p.Gly729Arg variant does not disrupt protein stability or thermostability (Bezerra GA et al., PMID: 32695416), functional studies in patient fibroblasts show elevated levels of 2-oxoadipate that was rescued with the expression of wildtype DHTKD1 (Danhauser K et al., PMID: 23141293). This variant also results in decreased catalytic efficiency for NADH production which impairs channeling of 2-oxoadipate dehydrogenase complex (OADHc) intermediates (Zhang X et al., PMID: 32303640); both studies indicate that this variant impacts protein function. Computational predictors are conflicting as to the impact of this variant on DHTKD1 function. This variant has been reported in the ClinVar database as a pathogenic variant by four submitters, likely pathogenic by eight submitters and a variant of uncertain significance by three submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017273	SCV004847983	uncertain significance	Inborn disorder of lysine and hydroxylysine metabolism	2016-11-11	criteria provided, single submitter	clinical testing	The p.Gly729Arg variant in DHTKD1 has been reported in 3 compound heterozygous individuals with 2-aminoadipic & 2-oxoadipic aciduria, one occurrence noted to be de novo (Danhauser 2012, Lee 2014) and has also been identified in 0.23% (151/66498) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs117225135). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Gly729Arg variant may impact protein function (Danhauser 2012). However, these types of assays may not accurately represent biological function. In addition, computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gly729Arg variant is uncertain.
OMIM	RCV000032764	SCV000056528	pathogenic	2-aminoadipic 2-oxoadipic aciduria	2012-12-07	no assertion criteria provided	literature only
Institute of Human Genetics, Cologne University	RCV000032764	SCV000787771	pathogenic	2-aminoadipic 2-oxoadipic aciduria	2018-04-25	no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319173	SCV004023199	likely pathogenic	Tip-toe gait	2022-11-15	no assertion criteria provided	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
Inherited Neuropathy Consortium Ii, University Of Miami	RCV003447099	SCV004174577	uncertain significance	Charcot-Marie-Tooth disease type 2A2	2016-01-06	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004748541	SCV005344451	likely pathogenic	DHTKD1-related disorder	2024-06-26	no assertion criteria provided	clinical testing	The DHTKD1 c.2185G>A variant is predicted to result in the amino acid substitution p.Gly729Arg. This variant has been reported in the compound heterozygous and homozygous states in several individuals diagnosed with 2-aminoadipic 2-oxoadipic aciduria (Danhauser et al. 2012. PubMed ID: 23141293; Hagen et al. 2015. PubMed ID: 25860818; Stiles et al. 2015. PubMed ID: 26141459; Boonsawat et al. 2019. PubMed ID: 30842647). This variant is reported in 0.27% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including several homozygous individuals in the most recent dataset (https://gnomad.broadinstitute.org/variant/10-12112930-G-A?dataset=gnomad_r4), indicating this variant is relatively common. These population data suggest there may be reduced expressivity of disease when this variant is present in the homozygous state. Given the evidence, we interpret this variant as likely pathogenic.