rs397515323

Positions:

• chrX-24503479-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_005391.5(PDK3):​c.473G>A​(p.Arg158His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PDK3 NM_005391.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 9.97

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant X-24503479-G-A is Pathogenic according to our data. Variant chrX-24503479-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 60682.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chrX-24503479-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDK3	NM_005391.5	c.473G>A	p.Arg158His	missense_variant	4/11	ENST00000379162.9
PDK3	NM_001142386.3	c.473G>A	p.Arg158His	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDK3	ENST00000379162.9	c.473G>A	p.Arg158His	missense_variant	4/11	1	NM_005391.5	P1
PDK3	ENST00000568479.2	c.473G>A	p.Arg158His	missense_variant	4/12
PDK3	ENST00000648777.1	c.473G>A	p.Arg158His	missense_variant, NMD_transcript_variant	4/12

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 6 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 07, 2019	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect PDK3 protein function (PMID: 23297365). This variant has been observed to segregate with X-linked Charcot-Marie-Tooth disease in families (PMID: 23297365, 26801680). ClinVar contains an entry for this variant (Variation ID: 60682). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 158 of the PDK3 protein (p.Arg158His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

The c.473G>A (p.R158H) alteration is located in exon 4 (coding exon 4) of the PDK3 gene. This alteration results from a G to A substitution at nucleotide position 473, causing the arginine (R) at amino acid position 158 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported to co-segregate with Charcot-Marie-Tooth disease in two families with different haplotypes (Kennerson, 2013; Kennerson, 2016). This amino acid position is highly conserved in available vertebrate species. Functional studies show a gain of function affect (Kennerson, 2013; Perez-Siles, 2016; Perez-Siles, 2020; Narayanan, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.78	P;.
Vest4		0.74
MutPred		0.87		Loss of MoRF binding (P = 0.0321);Loss of MoRF binding (P = 0.0321);
MVP		0.96
MPC		1.9
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs397515323; hg19: chrX-24521596; COSMIC: COSV64792933; COSMIC: COSV64792933;