rs121964992

Variant names:

• chr7-107917349-G-A
• rs121964992
• NM_000108.5:c.1123G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000108.5(DLD):​c.1123G>A​(p.Glu375Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: DLD NM_000108.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 10.0
• Publications: 12 publications found

Genes affected

DLD (HGNC:2898): (dihydrolipoamide dehydrogenase) This gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In homodimeric form, the encoded protein functions as a dehydrogenase and is found in several multi-enzyme complexes that regulate energy metabolism. However, as a monomer, this protein can function as a protease. Mutations in this gene have been identified in patients with E3-deficient maple syrup urine disease and lipoamide dehydrogenase deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

DLD Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pyruvate dehydrogenase E3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107917349-G-A is Pathogenic according to our data. Variant chr7-107917349-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLD	NM_000108.5	c.1123G>A	p.Glu375Lys	missense_variant	Exon 11 of 14	ENST00000205402.10	NP_000099.2
DLD	NM_001289751.1	c.1054G>A	p.Glu352Lys	missense_variant	Exon 10 of 13		NP_001276680.1
DLD	NM_001289752.1	c.979G>A	p.Glu327Lys	missense_variant	Exon 10 of 13		NP_001276681.1
DLD	NM_001289750.1	c.826G>A	p.Glu276Lys	missense_variant	Exon 9 of 12		NP_001276679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLD	ENST00000205402.10	c.1123G>A	p.Glu375Lys	missense_variant	Exon 11 of 14	1	NM_000108.5	ENSP00000205402.3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000955 AC: 24 AN: 251242 AF XY: 0.0000884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000575 AC: 84 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 60 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111986

Other (OTH) AF: 0.000149 AC: 9 AN: 60394

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000104 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E3 deficiency Pathogenic:7

Feb 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 15, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 30, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2020

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Nov 29, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

DLD-related disorder Pathogenic:2

Sep 13, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Inborn genetic diseases Pathogenic:1

May 30, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1123G>A (p.E375K) alteration is located in coding exon 11 of the DLD gene. This alteration results from a G to A substitution at nucleotide position 1123, causing the glutamic acid (E) at amino acid position 375 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.009% (25/282646) total alleles studied. The highest observed frequency was 0.222% (23/10366) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state and/or in conjunction with other DLD variants in individuals with features consistent with dihydrolipoamide dehydrogenase deficiency; in at least one instance, the variants were identified in trans (Hong, 1997; Cerna, 2001; Cameron, 2006; Haviv, 2014; Pronicka, 2016; Wongkittichote, 2023). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Ambry internal data; Brautigam, 2005; Ambrus, 2013; Ambrus, 2016). In multiple assays testing DLD function, this variant showed functionally abnormal results (Ambrus, 2011; Vaubel, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

See cases Pathogenic:1

Nov 18, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3, PS4, PM2, PM3, PP3 -

not provided Pathogenic:1

Apr 28, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 32445240, 30283815, 28771251, 21558426, 16770810) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Uncertain	2.4	M;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MVP		0.76
MPC		0.83
ClinPred		0.91	D
GERP RS		4.1
Varity_R		0.99
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121964992; hg19: chr7-107557794;