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

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185853	SCV000238804	pathogenic	not provided	2020-01-27	criteria provided, single submitter	clinical testing	Reported carrier frequency of 1 in 94 in the Ashkenazi Jewish population (Shaag et al., 1999); Functional studies of the G229C variant showed a decrease in the mitochondrial respiratory function relative to wild-type (Vaubel et al., 2011); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 24012808, 25333069, 25885067, 9934985, 20672374, 17404228, 10448086, 8968745, 30487145, 21558426, 21930696, 25356417, 23995961, 27544700, 16601893, 14765544, 24516753, 16770810, 15712224, 12925875, 9764998, 30264509, 23290025, 23478190, 31334547, 31980526, 31589614, 33083013)
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
Invitae	RCV000012744	SCV000820574	pathogenic	Maple syrup urine disease, type 3	2020-11-02	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
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000185853	SCV001446673	pathogenic	not provided	2020-10-23	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.
Natera, Inc.	RCV000012744	SCV001464055	pathogenic	Maple syrup urine disease, type 3	2020-09-16	no assertion criteria provided	clinical testing