chr10-12112930-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_018706.7(DHTKD1):​c.2185G>A​(p.Gly729Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00266 in 1,610,968 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0027 ( 11 hom. )

Consequence

DHTKD1
NM_018706.7 missense

Scores

4
6
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15U:6

Conservation

PhyloP100: 3.91
Variant links:
Genes affected
DHTKD1 (HGNC:23537): (dehydrogenase E1 and transketolase domain containing 1) This gene encodes a component of a mitochondrial 2-oxoglutarate-dehydrogenase-complex-like protein involved in the degradation pathways of several amino acids, including lysine. Mutations in this gene are associated with 2-aminoadipic 2-oxoadipic aciduria and Charcot-Marie-Tooth Disease Type 2Q. [provided by RefSeq, May 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5
Variant 10-12112930-G-A is Pathogenic according to our data. Variant chr10-12112930-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39564.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=9, Uncertain_significance=5, Pathogenic=3}.
BP4
Computational evidence support a benign effect (MetaRNN=0.11351588). . Strength limited to SUPPORTING due to the PP5.
BS2
High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DHTKD1NM_018706.7 linkuse as main transcriptc.2185G>A p.Gly729Arg missense_variant 13/17 ENST00000263035.9 NP_061176.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DHTKD1ENST00000263035.9 linkuse as main transcriptc.2185G>A p.Gly729Arg missense_variant 13/171 NM_018706.7 ENSP00000263035 P1
DHTKD1ENST00000448829.1 linkuse as main transcriptc.*45G>A 3_prime_UTR_variant 6/65 ENSP00000398482

Frequencies

GnomAD3 genomes
AF:
0.00186
AC:
283
AN:
152102
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000386
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000852
Gnomad ASJ
AF:
0.00259
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00344
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00166
AC:
412
AN:
248268
Hom.:
0
AF XY:
0.00176
AC XY:
236
AN XY:
134236
show subpopulations
Gnomad AFR exome
AF:
0.000559
Gnomad AMR exome
AF:
0.000474
Gnomad ASJ exome
AF:
0.00210
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.00143
Gnomad FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.00272
Gnomad OTH exome
AF:
0.00216
GnomAD4 exome
AF:
0.00275
AC:
4009
AN:
1458748
Hom.:
11
Cov.:
31
AF XY:
0.00273
AC XY:
1983
AN XY:
725616
show subpopulations
Gnomad4 AFR exome
AF:
0.000570
Gnomad4 AMR exome
AF:
0.000475
Gnomad4 ASJ exome
AF:
0.00230
Gnomad4 EAS exome
AF:
0.0000507
Gnomad4 SAS exome
AF:
0.00167
Gnomad4 FIN exome
AF:
0.0000937
Gnomad4 NFE exome
AF:
0.00323
Gnomad4 OTH exome
AF:
0.00261
GnomAD4 genome
AF:
0.00186
AC:
283
AN:
152220
Hom.:
1
Cov.:
33
AF XY:
0.00156
AC XY:
116
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.000385
Gnomad4 AMR
AF:
0.000851
Gnomad4 ASJ
AF:
0.00259
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000830
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00344
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00286
Hom.:
1
Bravo
AF:
0.00192
TwinsUK
AF:
0.00378
AC:
14
ALSPAC
AF:
0.00337
AC:
13
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00233
AC:
20
ExAC
AF:
0.00155
AC:
188
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00384
EpiControl
AF:
0.00275

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:15Uncertain:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

2-aminoadipic 2-oxoadipic aciduria Pathogenic:8
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 08, 2024Variant 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. -
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Pathogenic, no assertion criteria providedclinical testingInstitute of Human Genetics, Cologne UniversityApr 25, 2018- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This 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. -
Likely pathogenic, criteria provided, single submittercurationSIB Swiss Institute of BioinformaticsApr 16, 2018This 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. -
Likely pathogenic, criteria provided, single submitterclinical testingClinical Genomics Laboratory, Washington University in St. LouisOct 02, 2023The 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. -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 07, 2012- -
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaAug 20, 2021The 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. -
not provided Pathogenic:3Uncertain:3
Likely pathogenic, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaJul 27, 2015- -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 23, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 24, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2024DHTKD1: PS3:Supporting, BS1:Supporting -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 19, 2023Observed 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) -
Likely pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicOct 26, 2022BP4, PM3, PS3, PS4_moderate -
not specified Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesApr 27, 2019- -
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 28, 2022The 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. -
Tip-toe gait Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPractice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice PomarinoNov 15, 2022Hereditary 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. -
DHTKD1-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 26, 2024The 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. -
Charcot-Marie-Tooth disease type 2A2 Uncertain:1
Uncertain significance, no assertion criteria providedliterature onlyInherited Neuropathy Consortium Ii, University Of MiamiJan 06, 2016- -
Inborn disorder of lysine and hydroxylysine metabolism Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 11, 2016The 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.16
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.30
T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.97
D
M_CAP
Pathogenic
0.38
D
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-1.2
T
MutationAssessor
Uncertain
2.2
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-6.0
D
REVEL
Benign
0.23
Sift
Uncertain
0.0060
D
Sift4G
Benign
0.074
T
Polyphen
0.98
D
Vest4
0.82
MutPred
0.62
Gain of loop (P = 0.069);
MVP
0.39
MPC
0.20
ClinPred
0.041
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.76
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs117225135; hg19: chr10-12154929; COSMIC: COSV53805911; COSMIC: COSV53805911; API