rs1165981822

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_005391.5(PDK3):c.562G>A(p.Asp188Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,202,287 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000015 ( 0 hom. 6 hem. )

Consequence

PDK3
NM_005391.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.93

Publications

0 publications found

Variant links:

Genes affected

PDK3 (HGNC:8811): (pyruvate dehydrogenase kinase 3) The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2). It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the three pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

PDK3 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease X-linked dominant 6
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

PDK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.817

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK3	NM_005391.5 link	c.562G>A	p.Asp188Asn	missense_variant	Exon 5 of 11	ENST00000379162.9	NP_005382.1
PDK3	NM_001142386.3 link	c.562G>A	p.Asp188Asn	missense_variant	Exon 5 of 12		NP_001135858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PDK3	ENST00000379162.9 link	c.562G>A	p.Asp188Asn	missense_variant	Exon 5 of 11	1	NM_005391.5	ENSP00000368460.4
PDK3	ENST00000568479.2 link	c.562G>A	p.Asp188Asn	missense_variant	Exon 5 of 12	6		ENSP00000498864.1
PDK3	ENST00000648777.1 link	n.562G>A		non_coding_transcript_exon_variant	Exon 5 of 12			ENSP00000497727.1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111576

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000652

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

180075

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000147

AC:

AN:

1090711

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

356323

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26219

American (AMR)

AF:

0.00

AC:

AN:

35063

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19307

East Asian (EAS)

AF:

0.00

AC:

AN:

30032

South Asian (SAS)

AF:

0.00

AC:

AN:

53711

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4103

European-Non Finnish (NFE)

AF:

0.0000191

AC:

AN:

835953

Other (OTH)

AF:

0.00

AC:

AN:

45843

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000179

AC:

AN:

111576

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

33776

show subpopulations

African (AFR)

AF:

0.0000652

AC:

AN:

30658

American (AMR)

AF:

0.00

AC:

AN:

10461

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5980

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53156

Other (OTH)

AF:

0.00

AC:

AN:

1493

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 29, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.562G>A (p.D188N) alteration is located in exon 5 (coding exon 5) of the PDK3 gene. This alteration results from a G to A substitution at nucleotide position 562, causing the aspartic acid (D) at amino acid position 188 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease X-linked dominant 6

Uncertain:1

Sep 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid with asparagine at codon 188 of the PDK3 protein (p.Asp188Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PDK3-related conditions. 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

.;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

9.9

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.20

Sift

Benign

0.15

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.83

P;.

Vest4

0.66

MutPred

0.57

Gain of glycosylation at T190 (P = 0.1466);Gain of glycosylation at T190 (P = 0.1466);

MVP

0.72

MPC

1.4

ClinPred

0.97

GERP RS

5.6

Varity_R

0.77

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over