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

gnomAD frequency: 0.00016  dbSNP: rs121964990

Total submissions: 21

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 Laboratory Services, Illumina	RCV004528103	SCV000466235	pathogenic	DLD-related disorder	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	Pyruvate dehydrogenase E3 deficiency	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012744	SCV000820574	pathogenic	Pyruvate dehydrogenase E3 deficiency	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 229 of the DLD protein (p.Gly229Cys). This variant is present in population databases (rs121964990, gnomAD 0.6%). This missense change has been observed in individuals with dihydrolipoamide dehydrogenase deficiency (PMID: 21558426, 21930696, 23478190). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly194Cys. ClinVar contains an entry for this variant (Variation ID: 11966). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DLD function (PMID: 21558426, 21930696). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000012744	SCV000893733	pathogenic	Pyruvate dehydrogenase E3 deficiency	2022-01-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000012744	SCV001194203	pathogenic	Pyruvate dehydrogenase E3 deficiency	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	Pyruvate dehydrogenase E3 deficiency		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
Revvity Omics, Revvity	RCV000012744	SCV002020383	pathogenic	Pyruvate dehydrogenase E3 deficiency	2023-03-30	criteria provided, single submitter	clinical testing
DASA	RCV004528103	SCV002061158	pathogenic	DLD-related disorder	2022-01-05	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000012744	SCV004193949	pathogenic	Pyruvate dehydrogenase E3 deficiency	2024-03-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000012744	SCV004806081	pathogenic	Pyruvate dehydrogenase E3 deficiency	2024-03-25	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000012744	SCV005051752	pathogenic	Pyruvate dehydrogenase E3 deficiency	2024-02-01	criteria provided, single submitter	curation
Breakthrough Genomics, Breakthrough Genomics	RCV000012744	SCV005088828	pathogenic	Pyruvate dehydrogenase E3 deficiency	2020-04-12	criteria provided, single submitter	clinical testing	This variant was previously reported in patients with dihydrolipoamide dehydrogenase (DLD or E3) deficiency in homozygous and compound heterozygous state. In addition, this variant was also identified in a heterozygous state without a second variant [PMID's: 9934985, 23478190, 23995961] and reported as disease causing mutation located in NAD+ binding domain [PMID: 23478190]. This variant in the DLD gene has been reported with a carrier frequency of 1 in 94 in the Ashkenazi Jewish population [PMID: 9934985]. Functional studies on this variant p.Gly229Cys (represented as G194C) have shown to impairs DLD function and results in increased reactive oxygen species (ROS) generation in vitro and in yeast [PMID: 21558426, 21930696].
OMIM	RCV000012744	SCV000032979	pathogenic	Pyruvate dehydrogenase E3 deficiency	2011-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000012744	SCV000148070	pathogenic	Pyruvate dehydrogenase E3 deficiency	2014-04-02	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000012744	SCV000854707	pathogenic	Pyruvate dehydrogenase E3 deficiency	2018-06-04	no assertion criteria provided	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000012744	SCV001142375	pathogenic	Pyruvate dehydrogenase E3 deficiency	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	Pyruvate dehydrogenase E3 deficiency	2020-09-16	no assertion criteria provided	clinical testing