7-107915506-G-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000820574: Experimental studies have shown that this missense change affects DLD function (PMID:21558426, 21930696).; SCV001142375: 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).; SCV005088828: 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; SCV005849200: Experimental studies have shown that this missense change affects DLD function (Ambrus A, et al., 2011).; SCV006582075: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:21930696).; SCV000238804: Functional studies of the p.(G229C) variant showed a decrease in the mitochondrial respiratory function relative to wild-type. PMID:21930696; SCV000466235: 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).; SCV002061158: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:23478190, 21558426, 21930696) - PS3."".

• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, G2P, Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000820574: Experimental studies have shown that this missense change affects DLD function (PMID: 21558426, 21930696).; SCV001142375: 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).; SCV005088828: 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; SCV005849200: Experimental studies have shown that this missense change affects DLD function (Ambrus A, et al., 2011).; SCV006582075: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21930696).; SCV000238804: Functional studies of the p.(G229C) variant showed a decrease in the mitochondrial respiratory function relative to wild-type. PMID:21930696; SCV000466235: 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).; SCV002061158: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 23478190, 21558426, 21930696) - PS3."
• 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

Sel.	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	A0A024R713
	DLD	NM_001289751.1		c.616G>T	p.Gly206Cys	missense splice_region	Exon 8 of 13	NP_001276680.1	P09622
	DLD	NM_001289752.1		c.541G>T	p.Gly181Cys	missense splice_region	Exon 8 of 13	NP_001276681.1	P09622-3

Ensembl Transcripts

Sel.	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	P09622-1
	DLD	ENST00000451081.5	TSL:1	n.*428G>T		splice_region non_coding_transcript_exon	Exon 9 of 9	ENSP00000388077.1	F2Z2E3
	DLD	ENST00000451081.5	TSL:1	n.*428G>T		3_prime_UTR	Exon 9 of 9	ENSP00000388077.1	F2Z2E3

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
19	-	-	Pyruvate dehydrogenase E3 deficiency (19)
3	-	-	DLD-related disorder (3)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)

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;