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

gnomAD frequency: 0.00006  dbSNP: rs121964992

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185859	SCV000238810	pathogenic	not provided	2023-07-20	criteria provided, single submitter	clinical testing	Published 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as E340K; This variant is associated with the following publications: (PMID: 23995961, 27290639, 24012808, 21930696, 11687750, 9540846, 27544700, 20160912, 28771251, 30283815, 32445240, 16770810, 21558426)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012751	SCV000695409	pathogenic	Pyruvate dehydrogenase E3 deficiency	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 Laboratory Services, Illumina	RCV004528104	SCV000915197	pathogenic	DLD-related disorder	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012751	SCV000962796	pathogenic	Pyruvate dehydrogenase E3 deficiency	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 375 of the DLD protein (p.Glu375Lys). This variant is present in population databases (rs121964992, gnomAD 0.2%). This missense change has been observed in individuals with dihydrolipoamide dehydrogenase deficiency (PMID: 9540846, 11687750, 16770810, 18362926, 27290639). This variant is also known as Glu340Lys. ClinVar contains an entry for this variant (Variation ID: 11971). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DLD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DLD function (PMID: 18362926, 21558426, 21930696). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000012751	SCV001193900	likely pathogenic	Pyruvate dehydrogenase E3 deficiency	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
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251899	SCV002523349	pathogenic	See cases	2019-11-18	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2, PM3, PP3
Fulgent Genetics, Fulgent Genetics	RCV000012751	SCV002778733	pathogenic	Pyruvate dehydrogenase E3 deficiency	2022-01-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000012751	SCV004193952	pathogenic	Pyruvate dehydrogenase E3 deficiency	2024-03-24	criteria provided, single submitter	clinical testing
OMIM	RCV000012751	SCV000032986	pathogenic	Pyruvate dehydrogenase E3 deficiency	2006-07-15	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004528104	SCV005361732	pathogenic	DLD-related disorder	2024-04-05	no assertion criteria provided	clinical testing	The DLD c.1123G>A variant is predicted to result in the amino acid substitution p.Glu375Lys. This variant has been reported in many individuals with dihydrolipoamide dehydrogenase deficiency (also known as E340K; Hong et al 1997. PubMed ID: 9540846; Ambrus et al 2011. PubMed ID: 21558426; Ambrus et al 2013. PubMed ID: 24012808). This variant is reported in 0.22% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.