rs863224148

Variant names:

• chrX-19350033-C-T
• rs863224148
• NM_000284.4:c.214C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM6 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The c.214C>T (p.R72C) variant in PDHA1 has been reported in multiples males with pyruvate dehydrogenase deficiency with phenotypes ranging from childhood onset Leigh syndrome spectrum (PMID:8664900) to living into adulthood with ataxia, neuropathy, and dystonia (PMID:21914562). We did not come across any affected female case reports in this extensive literature review. This variant has been reported to be inherited from a healthy mother (PMID:10679936; case 3-4) and there have been several de novo case reports, as well. Indeed, this variant has been identified as a de novo occurrence (unconfirmed parental relationships) in at least three unrelated individuals with pyruvate dehydrogenase deficiency [PM6; Utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); PMID:10679936, case 3-2; PMID:10679936, case 3-3; PMID:21914562, case AM23]. Additionally, this variant has been seen in at least one other individual with documented decreased pyruvate dehydrogenase activity (PP4; Patient 3 in PMID:15384102 had Leigh syndrome and decreased total PDH complex activity (in native and DCA-activated states) in fibroblast cell line (<3rd percentile of controls). This variant is absent from gnomAD v2.1.1 (PM2). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.75, evidence that correlates with impact to PDHA1 function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for pyruvate dehydrogenase deficiency inherited in an X-linked manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2020. PDHA1-specific ACMG/AMP criteria applied: PM2, PM6, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA320653/MONDO:0019169/014

• Frequency: Genomes: not found (cov: 23)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 2.92

Genes affected

PDHA1 (HGNC:8806): (pyruvate dehydrogenase E1 subunit alpha 1) 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), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. 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 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHA1	NM_000284.4	c.214C>T	p.Arg72Cys	missense_variant	Exon 3 of 11	ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7	c.214C>T	p.Arg72Cys	missense_variant	Exon 3 of 11	1	NM_000284.4	ENSP00000394382.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:3

Dec 20, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PDHA1 c.214C>T (p.Arg72Cys) missense variant, also referred to in the literature as c.328C>T (p.Arg110Cys), results in the substitution of arginine at amino acid position 72 with a cysteine. Across a selection of the available literature, the c.214C>T variant was identified in a hemizygous state in eight male patients with pyruvate dehydrogenase deficiency (Lissens et al. 2000; Cameron et al. 2004; Head et al. 2004; Barnerias et al. 2010; Zhu et al. 2015). Several heterozygous carrier females have been identified with this variant, but their phenotypes were not described (Lissens et al. 2000; Cameron et al. 2004). Affected individuals presented with a range of phenotypes, including Leigh syndrome, hypotonia, dystonia, ataxia, MRI abnormalities, and elevated lactate and pyruvate in blood and CSF. The c.214C>T variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Evaluation of patient fibroblasts showed significantly decreased pyruvate dehydrogenase complex and pyruvate dehydrogenase E1 activity levels compared to controls (Lissens et al. 2000; Cameron et al. 2004; Head et al. 2004; Barnerias et al. 2010). Based on the available evidence, the c.214C>T (p.Arg72Cys) variant is classified as pathogenic for pyruvate dehydrogenase deficiency. -

Jan 03, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000214938, PMID:1301207, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.955, 3CNET: 0.913, PP3_P). A missense variant is a common mechanism associated with Pyruvate dehydrogenase E1-alpha deficiency (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 72 of the PDHA1 protein (p.Arg72Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pyruvate dehydrogenase E1-alpha deficiency (PMID: 1301207, 7887409, 10679936, 20002125, 25590979). ClinVar contains an entry for this variant (Variation ID: 214938). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PDHA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PDHA1 function (PMID: 1301207, 10679936). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 28, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10679936, 8664900, 15384102, 21914562, 20002125, 15473177, 7887409, 1301207, 25590979) -

Abnormality of the mitochondrion Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Apr 27, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pyruvate dehydrogenase complex deficiency Pathogenic:1

Oct 25, 2021

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.214C>T (p.R72C) variant in PDHA1 has been reported in multiples males with pyruvate dehydrogenase deficiency with phenotypes ranging from childhood onset Leigh syndrome spectrum (PMID: 8664900) to living into adulthood with ataxia, neuropathy, and dystonia (PMID: 21914562). We did not come across any affected female case reports in this extensive literature review. This variant has been reported to be inherited from a healthy mother (PMID: 10679936; case 3-4) and there have been several de novo case reports, as well. Indeed, this variant has been identified as a de novo occurrence (unconfirmed parental relationships) in at least three unrelated individuals with pyruvate dehydrogenase deficiency [PM6; Utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); PMID: 10679936, case 3-2; PMID: 10679936, case 3-3; PMID: 21914562, case AM23]. Additionally, this variant has been seen in at least one other individual with documented decreased pyruvate dehydrogenase activity (PP4; Patient 3 in PMID: 15384102 had Leigh syndrome and decreased total PDH complex activity (in native and DCA-activated states) in fibroblast cell line (<3rd percentile of controls). This variant is absent from gnomAD v2.1.1 (PM2). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.75, evidence that correlates with impact to PDHA1 function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for pyruvate dehydrogenase deficiency inherited in an X-linked manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2020. PDHA1-specific ACMG/AMP criteria applied: PM2, PM6, PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	.;.;.;D;D;D;D;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	5.1	H;H;.;.;.;H;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.2	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;.;.
Vest4		0.82
MutPred		0.97		Loss of MoRF binding (P = 0.0158);Loss of MoRF binding (P = 0.0158);.;.;.;Loss of MoRF binding (P = 0.0158);Loss of MoRF binding (P = 0.0158);Loss of MoRF binding (P = 0.0158);
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0

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

LitVar

Other links and lift over

dbSNP: rs863224148; hg19: chrX-19368151; COSMIC: COSV63327821; COSMIC: COSV63327821;