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NM_000108.5(DLD):c.685G>T (p.Gly229Cys) AND DLD-Related Disorders

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jan 5, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:

Allele description

NM_000108.5(DLD):c.685G>T (p.Gly229Cys)

DLD:dihydrolipoamide dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000108.5(DLD):c.685G>T (p.Gly229Cys)
Other names:
  • NC_000007.14:g.107915506G>T
  • NG_008045.1:g.29366G>T
  • NM_000108.5:c.685G>TMANE SELECT
  • NM_001289750.1:c.388G>T
  • NM_001289751.1:c.616G>T
  • NM_001289752.1:c.541G>T
  • NP_000099.2:p.Gly229Cys
  • NP_000099.2:p.Gly229Cys
  • NP_001276679.1:p.Gly130Cys
  • NP_001276680.1:p.Gly206Cys
  • NP_001276681.1:p.Gly181Cys
  • NC_000007.13:g.107555951G>T
  • NM_000108.3:c.685G>T
  • NM_000108.4:c.685G>T
  • P09622:p.Gly229Cys
  • c.685G>T (p.Gly229Cys)
Protein change:
G130C; GLY229CYS
UniProtKB: P09622#VAR_015820; OMIM: 238331.0006; dbSNP: rs121964990
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000108.5:c.685G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001289750.1:c.388G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001289751.1:c.616G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001289752.1:c.541G>T - missense variant - [Sequence Ontology: SO:0001583]


DLD-Related Disorders
MedGen: CN239383

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000466235Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)
(Apr 27, 2017)
germlineclinical testing

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

Citation Link,

criteria provided, single submitter

(ACMG Guidelines, 2015)
(Jan 5, 2022)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews.

Shaag A, Saada A, Berger I, Mandel H, Joseph A, Feigenbaum A, Elpeleg ON.

Am J Med Genet. 1999 Jan 15;82(2):177-82.

PubMed [citation]

Elevated plasma citrulline: look for dihydrolipoamide dehydrogenase deficiency.

Haviv R, Zeharia A, Belaiche C, Haimi Cohen Y, Saada A.

Eur J Pediatr. 2014 Feb;173(2):243-5. doi: 10.1007/s00431-013-2153-x. Epub 2013 Aug 31.

PubMed [citation]
See all PubMed Citations (8)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000466235.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)


Across a selection of available literature, the DLD c.685G>T (p.Gly229Cys) missense variant has been identified in a total of 27 patients with dihydrolipoamide dehydrogenase deficiency (also known as maple syrup urine disease type III), including 22 in a homozygous state, four in a compound heterozygous state, and one in a heterozygous state in whom a second variant was not identified (Shaag et al. 1999; Brassier et al. 2013; Haviv et al. 2014). The p.Gly229Cys variant was also identified in a heterozygous state in five unaffected family members. Control data are not available for this variant, which is reported at a frequency of 0.00042 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Gly229Cys variant is located in the NAD+ binding domain of the protein. Functional studies using biochemical and biophysical analyses demonstrated that the variant increases the generation of reactive oxygen species compared to the wild type enzyme (Ambrus et al. 2011). Based on the evidence, the p.Gly229Cys variant is classified as pathogenic for DLD-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From DASA, SCV002061158.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)


The c.685G>T;p.(Gly229Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 11966; PMID: 21930696; 23478190; 21558426; OMIM: 238331.0006) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 23478190, 21558426, 21930696) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (NAD + binding) - PM1. The variant is present at low allele frequencies population databases (rs121964990– gnomAD 0.001776%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly229Cys) was detected in trans with a pathogenic variant (PMID: 23995961) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: May 7, 2024