chr7-107917349-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3PM2PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000695409: 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)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

DLD
NM_000108.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 10.0

Publications

13 publications found

Variant links:

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

DLD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000695409: 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).; SCV000962796: Experimental studies have shown that this missense change affects DLD function (PMID: 18362926, 21558426, 21930696).; SCV001193900: 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. PMID: 23995961, 16442803, 21930696, 21558426, 18362926, 9540846, 11687750 and 16770810.; SCV001444226: In multiple assays testing DLD function, this variant showed functionally abnormal results (Ambrus, 2011; Vaubel, 2011).; SCV000915197: 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).

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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLD	NM_000108.5	MANE Select	c.1123G>A	p.Glu375Lys	missense	Exon 11 of 14	NP_000099.2	A0A024R713
DLD	NM_001289751.1		c.1054G>A	p.Glu352Lys	missense	Exon 10 of 13	NP_001276680.1	P09622
DLD	NM_001289752.1		c.979G>A	p.Glu327Lys	missense	Exon 10 of 13	NP_001276681.1	P09622-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLD	ENST00000205402.10	TSL:1 MANE Select	c.1123G>A	p.Glu375Lys	missense	Exon 11 of 14	ENSP00000205402.3	P09622-1
DLD	ENST00000880448.1		c.1105G>A	p.Glu369Lys	missense	Exon 11 of 14	ENSP00000550507.1
DLD	ENST00000880447.1		c.1099G>A	p.Glu367Lys	missense	Exon 11 of 14	ENSP00000550506.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

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:

AN:

251242

AF XY:

0.0000884

show subpopulations

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:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1111986

Other (OTH)

AF:

0.000149

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000104

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyruvate dehydrogenase E3 deficiency (7)

DLD-related disorder (2)

Inborn genetic diseases (1)

not provided (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.56

MetaSVM

Uncertain

0.082

MutationAssessor

Uncertain

2.4

PhyloP100

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.76

MPC

0.83

ClinPred

0.91

GERP RS

4.1

Varity_R

0.99

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over