ClinVar Miner

Submissions for variant NM_000108.5(DLD):c.685G>T (p.Gly229Cys) (rs121964990)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185853 SCV000238804 pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing The G229C variant in the DLD gene has been reported previously in individuals with dihydrolipoamide dehydrogenase deficiency and this mutation has a carrier frequency of 1 in 94 in the Ashkenazi Jewish population (Shaag et al., 1999). The G229C variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. This change occurs at a residue that is conserved across species. In silico analyses predict this variant is probably damaging to the protein structure/function. The G229C variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. We interpret G229C as a disease-causing variant.
Illumina Clinical Services Laboratory,Illumina RCV000301987 SCV000466235 pathogenic DLD-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000185853 SCV000511508 pathogenic not provided 2016-12-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000012744 SCV000695410 pathogenic Maple syrup urine disease, type 3 2016-10-27 criteria provided, single submitter clinical testing Variant summary: The DLD c.685G>T (p.Gly229Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 32/121202 control chromosomes (1 homozygote) at a frequency of 0.000264, which does not exceed the estimated maximal expected allele frequency of a pathogenic DLD variant (0.005). The variant has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000624277 SCV000741904 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000012744 SCV000820574 pathogenic Maple syrup urine disease, type 3 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 229 of the DLD protein (p.Gly229Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs121964990, ExAC 0.04%). This variant has been observed in many individuals and families affected with dihydrolipoamide dehydrogenase deficiency (PMID: 23478190, 21558426, 21930696). This variant is also known as Gly194Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 11966). Experimental studies have shown that this missense change impairs DLD function and increases reactive oxygen species (ROS) generation in vitro and in yeast (PMID: 21558426, 21930696). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000012744 SCV000893733 pathogenic Maple syrup urine disease, type 3 2018-10-31 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000012744 SCV001194203 pathogenic Maple syrup urine disease, type 3 2019-10-18 criteria provided, single submitter clinical testing NM_000108.3(DLD):c.685G>T(G229C, aka G194C) is classified as pathogenic in the context of dihydrolipoamide dehydrogenase deficiency. Sources cited for classification include the following: PMIDs: 16601893, 14765544, 23995961, 21930696, 21558426, 9934985. Classification of NM_000108.3(DLD):c.685G>T(G229C, aka G194C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Centogene AG - the Rare Disease Company RCV000012744 SCV001424402 pathogenic Maple syrup urine disease, type 3 criteria provided, single submitter clinical testing
OMIM RCV000012744 SCV000032979 pathogenic Maple syrup urine disease, type 3 2011-08-01 no assertion criteria provided literature only
GeneReviews RCV000012744 SCV000148070 pathogenic Maple syrup urine disease, type 3 2014-04-02 no assertion criteria provided literature only
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000012744 SCV000854707 pathogenic Maple syrup urine disease, type 3 2018-06-04 no assertion criteria provided clinical testing
Reproductive Health Research and Development,BGI Genomics RCV000012744 SCV001142375 pathogenic Maple syrup urine disease, type 3 2020-01-06 no assertion criteria provided curation NM_000108.3:c.685G>T in the DLD gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. Haviv R et al. reported that eight of 15 studied patients with dihydrolipoamide dehydrogenase deficiency were homozygous for the common G229C mutation and two were compound heterozygous for the G229C and Y35X mutations (PMID: 23995961). Functional studies using biochemical and biophysical analyses demonstrated that the variant increases the generation of reactive oxygen species compared to the wild type enzyme (PMID: 21558426). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PS3; PP4.

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