10-12094222-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_018706.7(DHTKD1):c.1309G>T(p.Glu437*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

DHTKD1
NM_018706.7 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:2

Conservation

PhyloP100: 9.83

Publications

2 publications found

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]

DHTKD1 Gene-Disease associations (from GenCC):

2-aminoadipic 2-oxoadipic aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
Charcot-Marie-Tooth disease axonal type 2Q
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

DHTKD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 10-12094222-G-T is Pathogenic according to our data. Variant chr10-12094222-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 574714.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHTKD1	NM_018706.7 link	c.1309G>T	p.Glu437*	stop_gained	Exon 7 of 17	ENST00000263035.9	NP_061176.4	Q96HY7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DHTKD1	ENST00000263035.9 link	c.1309G>T	p.Glu437*	stop_gained	Exon 7 of 17	1	NM_018706.7	ENSP00000263035.4	Q96HY7
DHTKD1	ENST00000415935.1 link	c.403G>T	p.Glu135*	stop_gained	Exon 3 of 3	2		ENSP00000400625.1	H7C1J3
DHTKD1	ENST00000465617.1 link	n.449G>T		non_coding_transcript_exon_variant	Exon 3 of 4	3
DHTKD1	ENST00000448829.1 link	c.-39G>T		upstream_gene_variant		5		ENSP00000398482.1	H7C149

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000596

AC:

AN:

251488

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000104

AC:

152

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000132

AC:

147

AN:

1112012

Other (OTH)

AF:

0.0000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

2-aminoadipic 2-oxoadipic aciduria

Pathogenic:5

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic: Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with recessive disease. However, two unrelated families with autosomal dominant Charcot-Marie-Tooth disease type 2Q have been reported to harbour NMD-predicted variants (PMID: 23141294, 28902413). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 7 of 17). (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (14 heterozygotes, 0 homozygotes). (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Less than 10 NMD-predicted variants have been reported (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in Clinvar once, as a heterozygote in a single patient with Charcot-Marie-Tooth and part of compound heterozygote in a patient with alpha-ketoadipic and alpha-aminoadipic aciduria (Clinvar, PMID: 25860818, 28902413). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Apr 15, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DHTKD1 c.1309G>T (p.Glu437X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6e-05 in 251488 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DHTKD1 causing 2-aminoadipic 2-oxoadipic aciduria (6e-05 vs 0.0011), allowing no conclusion about variant significance. c.1309G>T has been reported in the literature in individuals affected with 2-Aminoadipic 2-Oxoadipic Aciduria (Hagen_2015), Charcot-Marie-Tooth Type 2Q (Dohrn_2017) and Amyotrophic Lateral Sclerosis (Osmanovic_2022). These data indicate that the variant is very likely to be associated with disease. 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: 28902413, 25860818, 35052424). ClinVar contains an entry for this variant (Variation ID: 574714). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Glu437*) in the DHTKD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DHTKD1 are known to be pathogenic (PMID: 23141293, 25860818). This variant is present in population databases (rs138884194, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with alpha-aminoadipic and alpha-ketoadipic aciduria (PMID: 25860818). ClinVar contains an entry for this variant (Variation ID: 574714). For these reasons, this variant has been classified as Pathogenic. -

May 31, 2022

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 2020

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature termination codon at position 437 in exon 7 (of 17) of DHTKD1 (p.Glu437*). It is expected to result in an absent or disrupted protein product. Loss of function variants in DHTKD1 are known to be pathogenic (PMID: 23141293, 25860818 - PVS1). The variant is present in a large population cohort at a frequency of 0.006% (rs138884194, 18/282,894 alleles in gnomAD v2.1 - PM2). It has been reported compound heterozygous with a second pathogenic variant in a case diagnosed with alpha-aminoadipic and alpha-ketoadipic aciduria (PMID: 25860818 - PM3). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2, PM3. -

not provided

Pathogenic:1Uncertain:2

Oct 21, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DHTKD1: PVS1:Moderate -

Aug 17, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified with another DHTKD1 variant (phase unknown) in a patient with alpha-aminoadipic and alpha-ketoadipic aciduria (PMID: 25860818); Reported as a heterozygous variant in an individual with amyotrophic lateral sclerosis (PMID: 35052424) and in an individual with Charcot Marie Tooth disease (PMID: 28902413); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25860818, 35052424, 28902413) -

Inborn genetic diseases

Pathogenic:1

Mar 15, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1309G>T (p.E437*) alteration, located in exon 7 (coding exon 7) of the DHTKD1 gene, consists of a G to T substitution at nucleotide position 1309. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 437. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration co-occurred with a second alteration in the DHTKD1 gene in an individual with alpha-aminoadipic and alpha-ketoadipic aciduria; however, information of the phase of these alterations was not provided (Hagen, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

Charcot-Marie-Tooth disease axonal type 2Q

Pathogenic:1

Jul 17, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset and therefore considered benign. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000574714 /PMID: 25860818). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.8

Vest4

0.41

GERP RS

4.7

PromoterAI

-0.035

Neutral

(source)

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over