VCV000011965.4 - ClinVar

NM_000108.5(DLD):c.1463C>T (p.Pro488Leu)

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.

(3)

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.

Likely 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_000108.5(DLD):c.1463C>T (p.Pro488Leu)

Variation ID: 11965 Accession: VCV000011965.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.1 7: 107919098 (GRCh38) [ NCBI UCSC ] 7: 107559543 (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	Jul 12, 2015	Sep 16, 2024	Jun 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000108.5:c.1463C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000099.2:p.Pro488Leu	missense
NM_001289750.1:c.1166C>T	NP_001276679.1:p.Pro389Leu	missense
NM_001289751.1:c.1394C>T	NP_001276680.1:p.Pro465Leu	missense
NM_001289752.1:c.1319C>T	NP_001276681.1:p.Pro440Leu	missense
NC_000007.14:g.107919098C>T
NC_000007.13:g.107559543C>T
NG_008045.1:g.32958C>T
	P09622:p.Pro488Leu

... more HGVS ... less HGVS

Protein change

P488L, P465L, P389L, P440L

Other names

Canonical SPDI

NC_000007.14:107919097:C:T

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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA256133 UniProtKB: P09622#VAR_006908 OMIM: 238331.0002 dbSNP: rs121964988 VarSome

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.
DLD		-	-	GRCh38 GRCh37	638	674

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 E3 deficiency	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 12, 2024	RCV000012743.26

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.
Likely pathogenic (Jun 12, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Pyruvate dehydrogenase E3 deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005204418.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Publications: PubMed (7) PubMed: 16770810‚ 23290025‚ 9934985‚ 31334547‚ 27544700‚ 21558426‚ 8506365 Comment: Variant summary: DLD c.1463C>T (p.Pro488Leu) results in a non-conservative amino acid change located in the Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain (IPR004099) of the encoded protein … (more) Variant summary: DLD c.1463C>T (p.Pro488Leu) results in a non-conservative amino acid change located in the Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain (IPR004099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251298 control chromosomes. c.1463C>T has been reported in the literature in a compound heterozygous individual affected with Dihydrolipoamide Dehydrogenase Deficiency (MSUD Type 3) whose cells had 6% of the E3 activity of control cells, but normal citrate synthase activity (Liu_1993). This report suggests the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The purified protein results in <10% dihydrolipoamide dehydrogenase activity compared to the WT (e.g. Ambrus_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21558426, 16770810, 8506365, 23290025, 9934985). ClinVar contains an entry for this variant (Variation ID: 11965). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Likely pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pyruvate dehydrogenase E3 deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004193969.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jun 01, 1993)	no assertion criteria provided Method: literature only	DIHYDROLIPOAMIDE DEHYDROGENASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032978.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 12, 2015	Publications: PubMed (1) PubMed: 8506365 Comment on evidence: For discussion of the pro488-to-leu (P488L) mutation in the DLD gene that was found in a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900) by Liu … (more) For discussion of the pro488-to-leu (P488L) mutation in the DLD gene that was found in a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900) by Liu et al. (1993), see 238331.0001. (less)

Comment:

Variant summary: DLD c.1463C>T (p.Pro488Leu) results in a non-conservative amino acid change located in the Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain (IPR004099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251298 control chromosomes. c.1463C>T has been reported in the literature in a compound heterozygous individual affected with Dihydrolipoamide Dehydrogenase Deficiency (MSUD Type 3) whose cells had 6% of the E3 activity of control cells, but normal citrate synthase activity (Liu_1993). This report suggests the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The purified protein results in <10% dihydrolipoamide dehydrogenase activity compared to the WT (e.g. Ambrus_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21558426, 16770810, 8506365, 23290025, 9934985). ClinVar contains an entry for this variant (Variation ID: 11965). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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
Underlying molecular alterations in human dihydrolipoamide dehydrogenase deficiency revealed by structural analyses of disease-causing enzyme variants.	Szabo E	Human molecular genetics	2019	PMID: 31334547
Structural alterations induced by ten disease-causing mutations of human dihydrolipoamide dehydrogenase analyzed by hydrogen/deuterium-exchange mass spectrometry: Implications for the structural basis of E3 deficiency.	Ambrus A	Biochimica et biophysica acta	2016	PMID: 27544700
Leigh syndrome in a girl with a novel DLD mutation causing E3 deficiency.	Quinonez SC	Pediatric neurology	2013	PMID: 23290025
Stimulation of reactive oxygen species generation by disease-causing mutations of lipoamide dehydrogenase.	Ambrus A	Human molecular genetics	2011	PMID: 21558426
Novel mutations in dihydrolipoamide dehydrogenase deficiency in two cousins with borderline-normal PDH complex activity.	Cameron JM	American journal of medical genetics. Part A	2006	PMID: 16770810
Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews.	Shaag A	American journal of medical genetics	1999	PMID: 9934985
Identification of two missense mutations in a dihydrolipoamide dehydrogenase-deficient patient.	Liu TC	Proceedings of the National Academy of Sciences of the United States of America	1993	PMID: 8506365

Text-mined citations for rs121964988 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000108.5(DLD):c.1463C>T (p.Pro488Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121964988 ...