7-107901759-T-G

Variant names:

• chr7-107901759-T-G
• rs397514651
• NM_000108.5:c.140T>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000108.5(DLD):​c.140T>G​(p.Ile47Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I47T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLD NM_000108.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000108.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107901759-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 40188.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

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.140T>G	p.Ile47Arg	missense	Exon 3 of 14	NP_000099.2	A0A024R713
	DLD	NM_001289751.1		c.140T>G	p.Ile47Arg	missense	Exon 3 of 13	NP_001276680.1	P09622
	DLD	NM_001289752.1		c.140T>G	p.Ile47Arg	missense	Exon 3 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.140T>G	p.Ile47Arg	missense	Exon 3 of 14	ENSP00000205402.3	P09622-1
	DLD	ENST00000451081.5	TSL:1	n.140T>G		non_coding_transcript_exon	Exon 3 of 9	ENSP00000388077.1	F2Z2E3
	DLD	ENST00000880448.1		c.122T>G	p.Ile41Arg	missense	Exon 3 of 14	ENSP00000550507.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pyruvate dehydrogenase E3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.90		Gain of methylation at I47 (P = 0.0055)
MVP		0.98
MPC		1.0
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.99
gMVP		0.98
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397514651; hg19: chr7-107542204;