VCV000010878.10 - ClinVar

NM_000284.4(PDHA1):c.787C>G (p.Arg263Gly)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000284.4(PDHA1):c.787C>G (p.Arg263Gly)

Variation ID: 10878 Accession: VCV000010878.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp22.12 X: 19355713 (GRCh38) [ NCBI UCSC ] X: 19373831 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 13, 2014	Feb 14, 2024	Mar 14, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000284.4:c.787C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000275.1:p.Arg263Gly	missense
NM_001173454.2:c.901C>G	NP_001166925.1:p.Arg301Gly	missense
NM_001173455.2:c.808C>G	NP_001166926.1:p.Arg270Gly	missense
NM_001173456.2:c.694C>G	NP_001166927.1:p.Arg232Gly	missense
NC_000023.11:g.19355713C>G
NC_000023.10:g.19373831C>G
NG_016781.1:g.16821C>G
	P08559:p.Arg263Gly

... more HGVS ... less HGVS

Protein change

R263G, R270G, R301G, R232G

Other names

p.R263G:CGA>GGA

Canonical SPDI

NC_000023.11:19355712:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA121213 UniProtKB: P08559#VAR_004959 OMIM: 300502.0008 dbSNP: rs137853259 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 1508605 Fig. 4 to determine the location of this allele on the current reference sequence.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PDHA1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	577	798

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Pyruvate dehydrogenase E1-alpha deficiency	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 14, 2022	RCV000011625.21
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 2, 2021	RCV000196576.12

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 14, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Pyruvate dehydrogenase E1-alpha deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003444431.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 1508605‚ 7887409‚ 8504306‚ 19639391 Comment: This variant is also known as c.787C>G (p.Arg234Gly). This missense change has been observed in individual(s) with pyruvate dehydrogenase lipoic acid synthetase deficiency (PMID: 1508605, … (more) This variant is also known as c.787C>G (p.Arg234Gly). This missense change has been observed in individual(s) with pyruvate dehydrogenase lipoic acid synthetase deficiency (PMID: 1508605, 7887409, 8504306, 19639391). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 263 of the PDHA1 protein (p.Arg263Gly). ClinVar contains an entry for this variant (Variation ID: 10878). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). (less)
Pathogenic (May 20, 2019)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Pyruvate dehydrogenase E1-alpha deficiency (X-linked inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150199.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Sex: female Tissue: blood
Pathogenic (Dec 02, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000252030.16 First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023	Comment: Published functional studies, including enzymatic activity and immunoblot studies, demonstrate that pyruvate dehydrogenase is affected (Wexler et al., 1992); Not observed at significant frequency in … (more) Published functional studies, including enzymatic activity and immunoblot studies, demonstrate that pyruvate dehydrogenase is affected (Wexler et al., 1992); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19852779, 21846590, 1301207, 19639391, 30634555, 31130284, 33619735, 1508605, 9187674) (less)
Pathogenic (Aug 01, 1997)	no assertion criteria provided Method: literature only	PYRUVATE DEHYDROGENASE E1-ALPHA DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031857.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 13, 2014	Publications: PubMed (4) PubMed: 9266390‚ 1508605‚ 8504306‚ 3137520 Comment on evidence: Naito et al. (1997) stated that the ARG263GLY mutation was previously reported as ARG234GLY by Wexler et al. (1992) and Chun et al. (1993). In … (more) Naito et al. (1997) stated that the ARG263GLY mutation was previously reported as ARG234GLY by Wexler et al. (1992) and Chun et al. (1993). In 2 brothers with E1 deficiency (PDHAD; 312170) reported by Kerr et al. (1988), Wexler et al. (1992) identified an arg234-to-gly (R234G) substitution in the PDHA1 gene. Study of other members of the family supported X-linked inheritance. The mutation is located in a highly conserved region of the PDHA1 gene that contains both hydrophobic and positively charged amino acid residues. Variable expression of pyruvate dehydrogenase complex deficiency in this case, with normal enzyme activity in fibroblasts, might have been due to instability of the pyruvate dehydrogenase heterotetramer in specific tissues resulting from a disruption of alpha- and beta-subunit interaction. In a patient with PDHAD, Naito et al. (1997) identified a 787C-G transversion in exon 8 of the PDHA1 gene, resulting in an arg263-to-gly (R263G) substitution. His unaffected mother was heterozygous for the mutation. The patient showed delayed development, metabolic acidosis, and basal ganglia lesions on MRI, consistent with a clinical diagnosis of Leigh syndrome. His older brother reportedly had a similar syndrome. Thiamine therapy resulted in clinical improvement in the index patient. Functional studies of cells from the patient and his mother showed decreased affinity of the E1 subunit for thiamine pyrophosphate, a necessary coenzyme. Naito et al. (1997) suggested that variable expression of pyruvate dehydrogenase complex deficiencies may depend on surrounding concentrations of thiamine and thiamine pyrophosphate. (less)

Comment:

This variant is also known as c.787C>G (p.Arg234Gly). This missense change has been observed in individual(s) with pyruvate dehydrogenase lipoic acid synthetase deficiency (PMID: 1508605, 7887409, 8504306, 19639391). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 263 of the PDHA1 protein (p.Arg263Gly). ClinVar contains an entry for this variant (Variation ID: 10878). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").

Comment:

Published functional studies, including enzymatic activity and immunoblot studies, demonstrate that pyruvate dehydrogenase is affected (Wexler et al., 1992); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19852779, 21846590, 1301207, 19639391, 30634555, 31130284, 33619735, 1508605, 9187674)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A cognitively normal PDH-deficient 18-year-old man carrying the R263G mutation in the PDHA1 gene.	Bachmann-Gagescu R	Journal of inherited metabolic disease	2009	PMID: 19639391
Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency.	Naito E	Journal of inherited metabolic disease	1997	PMID: 9266390
Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex.	Chun K	American journal of human genetics	1995	PMID: 7887409
Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate dehydrogenase complex.	Chun K	Human molecular genetics	1993	PMID: 8504306
A mutation in the E1 alpha subunit of pyruvate dehydrogenase associated with variable expression of pyruvate dehydrogenase complex deficiency.	Wexler ID	Pediatric research	1992	PMID: 1508605
A deficiency of both subunits of pyruvate dehydrogenase which is not expressed in fibroblasts.	Kerr DS	Pediatric research	1988	PMID: 3137520

Text-mined citations for rs137853259 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000284.4(PDHA1):c.787C>G (p.Arg263Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137853259 ...