ClinVar Miner

Submissions for variant NM_000108.5(DLD):c.1123G>A (p.Glu375Lys) (rs121964992)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185859 SCV000238810 pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing The E375K pathogenic variant in the DLD gene has been published previously (in some reports as E340K using alternate nomenclature) in multiple unrelated patients with clinical and biochemical features of dihydrolipoamide dehydrogenase deficiency who were homozgyous for this variant or were compound heterozygous for E375K and a second DLD variant (Hong et al., 1997; Cameron et al., 2006; Haviv et al., 2014). In vitro and in vivo functional studies showed that the E375K (E340K) variant reduced the enzyme activity compared to wild type (Ambrus et al., 2011; Vaubel et al., 2011). The E375K variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E375K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Therefore, we interpret E375K as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012751 SCV000695409 pathogenic Maple syrup urine disease, type 3 2020-12-30 criteria provided, single submitter clinical testing Variant summary: DLD c.1123G>A (p.Glu375Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251282 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in DLD causing Dihydrolipoamide Dehydrogenase Deficiency (MSUD Type 3) (9.6e-05 vs 0.005), allowing no conclusion about variant significance. c.1123G>A has been reported in the literature in the compound heterozygous and homozygous state in multiple individuals affected with Dihydrolipoamide Dehydrogenase Deficiency (Hong_1997, Cerna_2001, Cameron_2006, Rapoport_2008, Ciara_2016). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies report experimental evidence evaluating an impact on protein function and results in reduction in DLD activity (Hong_1997, Cerna_2001, Cameron_2006, Rapoport_2008). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778816 SCV000915197 pathogenic DLD-Related Disorders 2017-09-13 criteria provided, single submitter clinical testing The DLD c.1123G>A (p.Glu375Lys) missense variant has been reported in at least five studies in which it is found in a total of five unrelated individuals including in a homozygous state in one infant of 12 months with Leigh syndrome and in a compound heterozygous state in four individuals with clinical and biochemical features of DLD deficiency (Hong et al. 1997; Cerna et al. 2001; Cameron et al. 2006; Haviv et al. 2014; Pronicka et al. 2016). The variant was also found in a heterozygous state in five unaffected family members (Hong et al. 1997; Cerna et al. 2001; Cameron et al. 2006). One of the compound heterozygous individuals carried the p.Glu375Lys variant in trans with a p.Ile47Thr variant which was also carried by a cousin diagnosed with DLD deficiency, in trans with a third variant (Cameron et al. 2006). All affected individuals displayed reduced DLD enzyme activity in muscle, lymphocytes and fibroblasts of between <5% and 14% of control values depending on the tissue, as well as reduced protein levels of up to 3% of controls. Pyruvate dehydrogenase complex (PDC) and alpha-ketoglutarate dehydrogenase complex activities from cultured skin fibroblasts were reduced to 12% and 6% of control values respectively. DLD protein levels were also reduced to 40% compared to control values (Hong et al. 1997; Cerna et al. 2001; Cameron et al. 2006). Reduced DLD protein levels and PDC activity to 25 ΓÇô 50% of control levels were also seen in the cultured skin fibroblasts of unaffected heterozygous family members (Hong et al. 1997; Cerna et al. 2001; Cameron et al. 2006). The p.Glu375Lys variant was absent from 20 controls but is reported at a frequency of 0.002266 in the Ashkenazi Jewish population of the Genome Aggregation Database. The Gln375 residue is highly conserved. Functional studies in E.coli, demonstrated that the p.Glu375Lys variant resulted in only a modest reduction in DLD activity compared to controls in contrast to activities measured in cell lines derived from patients, thought to be due to the temperature at which activity was being measured (Vaubel et al. 2011). In yeast, variant DLD expression levels were shown to be similar to wild type (Vaubel et al. 2011). In E.coli JM83 cells, the variant protein did result in a significantly increased rate of reactive oxygen species and hydrogen peroxide generation compared to wildtype (Ambrus et al. 2011). Structural studies using HDX mass spectrometry of the variant protein transfected into E. coli demonstrated that the p.Glu375Lys variant results in considerable steric and charge modulations near the C-terminus of the protein (Ambrus et al. 2016). Based on the collective evidence, the 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.
Invitae RCV000012751 SCV000962796 likely pathogenic Maple syrup urine disease, type 3 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 375 of the DLD protein (p.Glu375Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs121964992, ExAC 0.01%). This variant has been observed in several individuals affected with dihydrolipoamide dehydrogenase deficiency (PMID: 9540846, 16770810, 27290639, 11687750, 18362926). This variant is also known as Glu340Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 11971). Experimental studies have shown that this missense change alters protein function (PMID: 18362926, 21930696, 21558426). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Women's Health, Inc. RCV000012751 SCV001193900 likely pathogenic Maple syrup urine disease, type 3 2020-01-03 criteria provided, single submitter clinical testing NM_000108.3(DLD):c.1123G>A(E375K) is classified as likely pathogenic in the context of dihydrolipoamide dehydrogenase deficiency. Sources cited for classification include the following: PMID: 23995961, 16442803, 21930696, 21558426, 18362926, 9540846, 11687750 and 16770810. Classification of NM_000108.3(DLD):c.1123G>A(E375K) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.
Ambry Genetics RCV001266054 SCV001444226 pathogenic Inborn genetic diseases 2017-11-11 criteria provided, single submitter clinical testing
OMIM RCV000012751 SCV000032986 pathogenic Maple syrup urine disease, type 3 2006-07-15 no assertion criteria provided literature only

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