Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine (exon 13). (N) 0252 - Variant is homozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (pyridine nucleotide-disulphide oxidoreductase, dimerisation domain; PDB). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as homozygous in multiple patients with deficiency in dihydrolipoamide dehydrogenase (DLD) and/or pyruvate dehydrogenase complex (PDHc) (PMIDs: 10448086, 21996136, 23995961). (P) 1001 - Strong functional evidence supporting abnormal protein function. DLD activity level was reduced in patients (PMIDs: 10448086, 23995961). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
ClinVar Genomic variation as it relates to human health
NM_000108.5(DLD):c.1436A>T (p.Asp479Val)
Germline
Classification
Help
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.
(6)
Help
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/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000108.5(DLD):c.1436A>T (p.Asp479Val)
Variation ID: 40186 Accession: VCV000040186.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.1 7: 107919071 (GRCh38) [ NCBI UCSC ] 7: 107559516 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 18, 2016 Apr 6, 2024 Mar 17, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000108.5:c.1436A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000099.2:p.Asp479Val missense NM_001289750.1:c.1139A>T NP_001276679.1:p.Asp380Val missense NM_001289751.1:c.1367A>T NP_001276680.1:p.Asp456Val missense NM_001289752.1:c.1292A>T NP_001276681.1:p.Asp431Val missense NC_000007.14:g.107919071A>T NC_000007.13:g.107559516A>T NG_008045.1:g.32931A>T P09622:p.Asp479Val - Protein change
- D479V, D456V, D431V, D380V
- Other names
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- Canonical SPDI
- NC_000007.14:107919070:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2024 | RCV000033216.37 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase E3 deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Hadassah Hebrew University Medical Center
Accession: SCV004099502.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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Likely pathogenic
(Sep 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase E3 deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003828918.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase E3 deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767867.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine (exon 13). (N) 0252 - Variant is homozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (pyridine nucleotide-disulphide oxidoreductase, dimerisation domain; PDB). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as homozygous in multiple patients with deficiency in dihydrolipoamide dehydrogenase (DLD) and/or pyruvate dehydrogenase complex (PDHc) (PMIDs: 10448086, 21996136, 23995961). (P) 1001 - Strong functional evidence supporting abnormal protein function. DLD activity level was reduced in patients (PMIDs: 10448086, 23995961). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Pyruvate dehydrogenase E3 deficiency
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001406862.2
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 479 of the DLD protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 479 of the DLD protein (p.Asp479Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dihydrolipoamide dehydrogenase deficiency (PMID: 10448086, 21996136, 23995961). This variant is also known as p.Asp444Val. ClinVar contains an entry for this variant (Variation ID: 40186). 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 DLD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DLD function (PMID: 17404228, 21558426, 21930696, 27544700). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Pyruvate dehydrogenase E3 deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804871.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Apr 10, 2007)
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no assertion criteria provided
Method: literature only
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DIHYDROLIPOAMIDE DEHYDROGENASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000057068.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 18, 2016 |
Comment on evidence:
In a 9-month-old girl of Muslim origin with a severe neurodegenerative form of dihydrolipoamide dehydrogenase deficiency (DLDD; 246900), Shany et al. (1999) identified a homozygous … (more)
In a 9-month-old girl of Muslim origin with a severe neurodegenerative form of dihydrolipoamide dehydrogenase deficiency (DLDD; 246900), Shany et al. (1999) identified a homozygous 1436A-T transversion in the DLD gene, resulting in an asp479-to-val (D479V) substitution, which is a D444V change in the processed protein (Odievre et al., 2005). The substitution occurs in the interface domain of the DLD dimer, which was postulated to perturb the stability of the homodimer. The patient reported by Shany et al. (1999) presented on the third day of life with apathy, poor feeding, and lethargy. Laboratory studies showed hypoglycemia and severe lactic acidosis, but normal levels of branched-chain keto acids and alpha-ketoglutarate. Muscle biopsy showed no activity of the pyruvate dehydrogenase complex, severely decreased activity of the alpha-ketoglutarate dehydrogenase complex (2%), and decreased DLD activity at 15% of controls. Each of her unaffected parents had about 50% reduced DLD protein activity. She had recurrent episodes of metabolic acidosis, often triggered by infection. Clinical features included microcephaly, lack of psychomotor development, blindness, deafness, hypotonia, brisk reflexes, and mild hypertrophic cardiomyopathy. Shany et al. (1999) noted that the phenotypic severity in this patient was not correlated with residual DLD protein activity, since the G229C mutation (238331.0006) was associated with even less activity (7%), but a milder phenotype. Babady et al. (2007) found that the D444V mutant protein had increased proteolytic activity compared to wildtype and that this proteolytic activity correlated with the monomer fraction of the mutant DLD protein. The appearance of this proteolytic activity may have contributed to the phenotypic severity. (less)
|
Comment:
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 479 of the DLD protein (p.Asp479Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dihydrolipoamide dehydrogenase deficiency (PMID: 10448086, 21996136, 23995961). This variant is also known as p.Asp444Val. ClinVar contains an entry for this variant (Variation ID: 40186). 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 DLD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DLD function (PMID: 17404228, 21558426, 21930696, 27544700). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as 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:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine (exon 13). (N) 0252 - Variant is homozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (pyridine nucleotide-disulphide oxidoreductase, dimerisation domain; PDB). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as homozygous in multiple patients with deficiency in dihydrolipoamide dehydrogenase (DLD) and/or pyruvate dehydrogenase complex (PDHc) (PMIDs: 10448086, 21996136, 23995961). (P) 1001 - Strong functional evidence supporting abnormal protein function. DLD activity level was reduced in patients (PMIDs: 10448086, 23995961). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 479 of the DLD protein (p.Asp479Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dihydrolipoamide dehydrogenase deficiency (PMID: 10448086, 21996136, 23995961). This variant is also known as p.Asp444Val. ClinVar contains an entry for this variant (Variation ID: 40186). 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 DLD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DLD function (PMID: 17404228, 21558426, 21930696, 27544700). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Elevated plasma citrulline: look for dihydrolipoamide dehydrogenase deficiency. | Haviv R | European journal of pediatrics | 2014 | PMID: 23995961 |
| The phosphorescence oxygen analyzer as a screening tool for disorders with impaired lymphocyte bioenergetics. | Al-Jasmi F | Molecular genetics and metabolism | 2011 | PMID: 21996136 |
| Mutations in the dimer interface of dihydrolipoamide dehydrogenase promote site-specific oxidative damages in yeast and human cells. | Vaubel RA | The Journal of biological chemistry | 2011 | PMID: 21930696 |
| Stimulation of reactive oxygen species generation by disease-causing mutations of lipoamide dehydrogenase. | Ambrus A | Human molecular genetics | 2011 | PMID: 21558426 |
| Cryptic proteolytic activity of dihydrolipoamide dehydrogenase. | Babady NE | Proceedings of the National Academy of Sciences of the United States of America | 2007 | PMID: 17404228 |
| A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene (DLD) resulting in an atypical form of alpha-ketoglutarate dehydrogenase deficiency. | Odièvre MH | Human mutation | 2005 | PMID: 15712224 |
| Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain. | Shany E | Biochemical and biophysical research communications | 1999 | PMID: 10448086 |
Text-mined citations for rs397514649 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.