NM_000108.5(DLD):c.104dup (p.Tyr35Ter) AND Maple syrup urine disease, type 3

Clinical significance:Pathogenic (Last evaluated: Jul 21, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000409901.11

Allele description [Variation Report for NM_000108.5(DLD):c.104dup (p.Tyr35Ter)]

NM_000108.5(DLD):c.104dup (p.Tyr35Ter)

Gene:
DLD:dihydrolipoamide dehydrogenase [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
7q31.1
Genomic location:
Preferred name:
NM_000108.5(DLD):c.104dup (p.Tyr35Ter)
HGVS:
  • NC_000007.14:g.107893264dup
  • NG_008045.1:g.7124dup
  • NM_000108.5:c.104dupMANE SELECT
  • NM_001289750.1:c.-45dup
  • NM_001289751.1:c.104dup
  • NM_001289752.1:c.104dup
  • NP_000099.2:p.Tyr35Ter
  • NP_001276680.1:p.Tyr35Ter
  • NP_001276681.1:p.Tyr35Ter
  • NC_000007.13:g.107533708_107533709insA
  • NC_000007.13:g.107533709dup
  • NM_000108.3:c.104dup
  • NM_000108.3:c.104dupA
  • NM_000108.4:c.104dup
  • NM_000108.4:c.104dupA
  • NM_000108.5:c.104dupAMANE SELECT
Protein change:
Y35*
Links:
OMIM: 238331.0003; dbSNP: rs753234219
NCBI 1000 Genomes Browser:
rs753234219
Molecular consequence:
  • NM_001289750.1:c.-45dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000108.5:c.104dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001289751.1:c.104dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001289752.1:c.104dup - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Maple syrup urine disease, type 3 (MSUD3)
Synonyms:
MAPLE SYRUP URINE DISEASE, TYPE III; DIHYDROLIPOAMIDE DEHYDROGENASE DEFICIENCY; E3 DEFICIENCY; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009529; MedGen: CN043137; Orphanet: 2394; Orphanet: 765; OMIM: 246900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000032980OMIMno assertion criteria providedPathogenic
(Mar 1, 2005)
germlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

SCV001194023Myriad Women's Health, Inc.criteria provided, single submitter
Pathogenic
(Dec 17, 2019)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001219534Invitaecriteria provided, single submitter
Pathogenic
(Jul 21, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001337760Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jan 10, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV001464049Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Leigh disease with deficiency of lipoamide dehydrogenase: treatment failure with dichloroacetate.

Craigen WJ.

Pediatr Neurol. 1996 Jan;14(1):69-71.

PubMed [citation]
PMID:
8652022

Lipoamide dehydrogenase deficiency in Ashkenazi Jews: an insertion mutation in the mitochondrial leader sequence.

Elpeleg ON, Shaag A, Glustein JZ, Anikster Y, Joseph A, Saada A.

Hum Mutat. 1997;10(3):256-7. No abstract available.

PubMed [citation]
PMID:
9298831
See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000032980.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)

Description

In a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900), who was originally reported by Craigen (1996), Hong et al. (1996) identified compound heterozygosity for 2 mutations in the DLD gene: a 1-bp insertion (105insA) in the last codon of the leader sequence predicted to result in a frameshift and premature termination (Y35X), and an arg495-to-gly (R495G; 238331.0004) substitution (R460G in the processed protein, Odievre et al., 2005). The patient had developmental delay, hypotonia, metabolic acidosis (elevated serum lactate and pyruvate), a history of transient neonatal hypoglycemia, and features of Leigh syndrome; she died at age 28 months. Plasma amino acid analysis in the patient initially showed increased leucine, isoleucine, and valine. Urine organic acid analysis showed mild to moderate increases of lactic, 2-hydroxybutyric, 3-hydroxybutyric, alpha-ketoglutaric, and 3-hydroxyisovaleric acids. She died at age 28 months. Activities of the PDC and E3 in patient lymphocytes were 26% and 2% of control values, respectively, and in patient fibroblasts were 11% and 14%, respectively. KGDC activity in fibroblasts was 20%. Corresponding values in the clinically unaffected parents were about 50% of normal, except for KGDC, which was normal. These findings suggested that a partial reduction in E3 is not rate-limiting for KGDC activity in fibroblasts. Glycine was also not increased in the patient.

In 2 unrelated patients of Ashkenazi-Jewish origin with DLDD, Elpeleg et al. (1997) identified the 105insA mutation in the DLD gene. The 2 patients were heterozygotes for the mutation; no other mutation was identified in the coding region. Heterozygosity for the 105insA mutation was also identified in the cDNA of the father and 1 brother of patient 1, and in the mother and 1 sister of patient 2. Because the enzymatic activity of lipoamide dehydrogenase in muscle tissue of both patients was reduced to 8 to 20% of the control mean, Elpeleg et al. (1997) presumed that both patients were compound heterozygotes for this and another unidentified mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Myriad Women's Health, Inc., SCV001194023.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

NM_000108.3(DLD):c.104dupA(Y35*) is classified as pathogenic in the context of dihydrolipoamide dehydrogenase deficiency. Sources cited for classification include the following: PMID 9298831 and 8968745. Classification of NM_000108.3(DLD):c.104dupA(Y35*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001219534.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Tyr35*) in the DLD gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs753234219, ExAC 0.02%). This variant has been observed in multiple individuals affected with dihydrolipoamide dehydrogenase deficiency (PMID: 8968745, 9934985). ClinVar contains an entry for this variant (Variation ID: 370072). Loss-of-function variants in DLD are known to be pathogenic (PMID: 8968745, 9934985). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001337760.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: DLD c.104dupA (p.Tyr35X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 250616 control chromosomes (gnomAD). c.104dupA has been reported in the literature in individuals (in compound heterozygous state) affected with Dihydrolipoamide Dehydrogenase Deficiency (MSUD Type 3) (Hong_1996, Shaag_1999). These data indicate that the variant may be associated with disease. Biochemical studies report this variant effect results in decreasing normal activity (Hong_1996, Shaag_1999). One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001464049.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 6, 2021

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