NM_000284.4(PDHA1):c.379C>T (p.Arg127Trp) AND Pyruvate dehydrogenase E1-alpha deficiency

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Feb 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001731151.12

Allele description [Variation Report for NM_000284.4(PDHA1):c.379C>T (p.Arg127Trp)]

NM_000284.4(PDHA1):c.379C>T (p.Arg127Trp)

Gene:

PDHA1:pyruvate dehydrogenase E1 subunit alpha 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp22.12

Genomic location:

Preferred name:

NM_000284.4(PDHA1):c.379C>T (p.Arg127Trp)

HGVS:

NC_000023.11:g.19351368C>T
NG_016781.1:g.12476C>T
NM_000284.3:c.379C>T
NM_000284.4:c.379C>TMANE SELECT
NM_001173454.2:c.493C>T
NM_001173455.2:c.400C>T
NM_001173456.2:c.379C>T
NP_000275.1:p.Arg127Trp
NP_001166925.1:p.Arg165Trp
NP_001166926.1:p.Arg134Trp
NP_001166927.1:p.Arg127Trp
NC_000023.10:g.19369486C>T
NM_000284.4:c.379C>T
NM_001173454.1:c.493C>T

Protein change:

R127W

Links:

dbSNP: rs199959402

NCBI 1000 Genomes Browser:

rs199959402

Molecular consequence:

NM_000284.4:c.379C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173454.2:c.493C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173455.2:c.400C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173456.2:c.379C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

Condition(s)

Name:: Pyruvate dehydrogenase E1-alpha deficiency (PDHAD)
Synonyms:: X-linked Leigh syndrome; ATAXIA, INTERMITTENT, WITH PYRUVATE DEHYDROGENASE DEFICIENCY; ATAXIA WITH LACTIC ACIDOSIS I; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010717; MedGen: C1839413; OMIM: 312170

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PREDICTED: Oryzias latipes HEAT repeat containing 3 (heatr3), transcript variant...
PREDICTED: Oryzias latipes HEAT repeat containing 3 (heatr3), transcript variant X2, mRNA
gi|1343945740|ref|XM_011493677.3|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001981598	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 19, 2021)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8024267, 25741868
SCV002570021	Center of Excellence for Medical Genomics, Chulalongkorn University	no assertion criteria provided	Pathogenic (Sep 8, 2002)	de novo	research
SCV002762707	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (May 6, 2022)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10679936, 16713755, 21914562, 32005694, 8024267 Citation Link,
SCV003444628	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 6, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8024267, 10679936, 25356417, 32005694, 21914562, 28492532
SCV003841519	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8024267, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Females with PDHA1 gene mutations: a diagnostic challenge.

Willemsen M, Rodenburg RJ, Teszas A, van den Heuvel L, Kosztolanyi G, Morava E.

Mitochondrion. 2006 Jun;6(3):155-9. Epub 2006 May 19.

PubMed [citation]

PMID:: 16713755

Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency.

Lissens W, De Meirleir L, Seneca S, Liebaers I, Brown GK, Brown RM, Ito M, Naito E, Kuroda Y, Kerr DS, Wexler ID, Patel MS, Robinson BH, Seyda A.

Hum Mutat. 2000;15(3):209-19. Review.

PubMed [citation]

PMID:: 10679936

See all PubMed Citations (8)

Details of each submission

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV001981598.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Center of Excellence for Medical Genomics, Chulalongkorn University, SCV002570021.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV002762707.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The PDHA1 c.379C>T (p.Arg127Trp) missense variant results in the substitution of arginine at amino acid position 127 with tryptophan. This variant has been reported in five studies in a total of six affected probands, including in four affected females in a heterozygous state (Fujii et al. 1994, Lissens et al. 2000; Willemsen et al. 2006, Imbard et al. 2011; Dong et al. 2020). Of these, three cases were confirmed to have a pyruvate dehydrogenase complex deficiency and a phenotype consistent with disease (Fujii et al. 1994, Willemsen et al. 2006, Imbard et al. 2011). Segregation was reported in one family comprising of a mother with a milder phenotype of intellectual disability, truncal ataxia, and dysarthria and two sons with a severe metabolic acidosis, both of which died in infancy. Methylation studies demonstrated skewed X-inactivation in the mother's fibroblast cells (Fujii et al. 1994). Willemsen et al. also reported skewed inactivation of the maternal X allele of above 90% in a female proband with a severe phenotype including neonatal muscle hypotonia and psycho-motor delays from three months of age, and microcephaly and tetraspasticity with neurological signs of pyramidal tract involvement from the age of 12 months (Willemsen et al. 2006). This variant is reported in the Genome Aggregation Database in one allele in a female individual at a frequency of 0.000032 in the African/African American population (version 3.1.2). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.379C>T (p.Arg127Trp) variant is classified as likely pathogenic for primary pyruvate dehydrogenase complex deficiency.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003444628.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 127 of the PDHA1 protein (p.Arg127Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of pyruvate dehydrogenase lipoic acid synthetase deficiency (PMID: 8024267, 10679936, 21914562, 25356417, 32005694). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg98Trp. ClinVar contains an entry for this variant (Variation ID: 214940). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PDHA1 protein function. This variant disrupts the p.Arg127 amino acid residue in PDHA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21914562). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003841519.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 8024267). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000214940) and a different missense change at the same codon (p.Arg127Gln / ClinVar ID: VCV000871395) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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