7-107915506-G-T

Variant names:

• chr7-107915506-G-T
• rs121964990
• NM_000108.5:c.685G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_000108.5(DLD):​c.685G>T​(p.Gly229Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,613,460 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DLD NM_000108.5 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 10.0
• Publications: 32 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: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-107915506-G-T is Pathogenic according to our data. Variant chr7-107915506-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000108.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLD	NM_000108.5	MANE Select	c.685G>T	p.Gly229Cys	missense splice_region	Exon 9 of 14	NP_000099.2
	DLD	NM_001289751.1		c.616G>T	p.Gly206Cys	missense splice_region	Exon 8 of 13	NP_001276680.1
	DLD	NM_001289752.1		c.541G>T	p.Gly181Cys	missense splice_region	Exon 8 of 13	NP_001276681.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLD	ENST00000205402.10	TSL:1 MANE Select	c.685G>T	p.Gly229Cys	missense splice_region	Exon 9 of 14	ENSP00000205402.3
	DLD	ENST00000451081.5	TSL:1	n.*428G>T		splice_region non_coding_transcript_exon	Exon 9 of 9	ENSP00000388077.1
	DLD	ENST00000451081.5	TSL:1	n.*428G>T		3_prime_UTR	Exon 9 of 9	ENSP00000388077.1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152028 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000326 AC: 82 AN: 251208 AF XY: 0.000346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000135 AC: 198 AN: 1461432 Hom.: 0 Cov.: 31 AF XY: 0.000140 AC XY: 102 AN XY: 727018

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00482 AC: 126 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5762

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111794

Other (OTH) AF: 0.000381 AC: 23 AN: 60376

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152028 Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74266

African (AFR) AF: 0.00 AC: 0 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000242 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E3 deficiency Pathogenic:19

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mar 30, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.685G>T(p.Gly229Cys) variant in DLD gene has been reported previously in multiple individuals affected with Dihydrolipoamide dehydrogenase deficiency (Haviv R, et al., 2014; Brassier A, et al., 2013; Hong YS, et al., 2003). This variant has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects DLD function (Ambrus A, et al., 2011). The p.Gly229Cys variant is present with allele frequency of 0.03% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on DLD gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 229 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. In absence of another reportable variant in DLD gene, the molecular diagnosis is not confirmed.

Apr 12, 2020

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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].

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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.

Jun 04, 2018

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 27, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Apr 02, 2014

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Oct 18, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DLD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DLD function (PMID: 21558426, 21930696). For these reasons, this variant has been classified as Pathogenic.

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Nov 25, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.014%). Predicted Consequence/Location: Missense variant. The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21930696). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.68 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011966 /PMID: 9934985 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3,PP1,PM3(strong),PP1,PM2

not provided Pathogenic:3

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported carrier frequency of 1 in 94 in the Ashkenazi Jewish population (PMID: 9934985); Functional studies of the p.(G229C) variant showed a decrease in the mitochondrial respiratory function relative to wild-type (PMID: 21930696); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24012808, 25333069, 25885067, 9934985, 20672374, 17404228, 10448086, 8968745, 30487145, 34745891, 35379322, 21558426, 25356417, 23995961, 27544700, 37701333, 16601893, 14765544, 24516753, 16770810, 15712224, 12925875, 9764998, 30264509, 23290025, 23478190, 31334547, 31980526, 31589614, 33083013, 32778825, 34023347, 21930696)

DLD-related disorder Pathogenic:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Apr 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DLD c.685G>T variant is predicted to result in the amino acid substitution p.Gly229Cys. This variant has been reported to be causative for dihydrolipoamide dehydrogenase deficiency and is commonly found in individuals with Ashkenazi Jewish or Arab ancestry (see for example, Shaag et al., 1999. PubMed ID: 9934985; Brassier et al. 2013. PubMed ID: 23478190). This variant is reported in 0.66% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.

Inborn genetic diseases Pathogenic:1

Sep 07, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		10
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.91
MPC		0.80
ClinPred		0.64	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.96
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.020		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: rs121964990; hg19: chr7-107555951;