rs753234219

Positions:

• chr7-107893263-T-TA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000108.5(DLD):​c.104dup​(p.Tyr35Ter) variant causes a stop gained, frameshift change. The variant allele was found at a frequency of 0.000011 in 1,460,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y35Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: DLD NM_000108.5 stop_gained, frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.30

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107893263-T-TA is Pathogenic according to our data. Variant chr7-107893263-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 370072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLD	NM_000108.5	c.104dup	p.Tyr35Ter	stop_gained, frameshift_variant	2/14	ENST00000205402.10
DLD	NM_001289751.1	c.104dup	p.Tyr35Ter	stop_gained, frameshift_variant	2/13
DLD	NM_001289752.1	c.104dup	p.Tyr35Ter	stop_gained, frameshift_variant	2/13
DLD	NM_001289750.1	c.-45dup		5_prime_UTR_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLD	ENST00000205402.10	c.104dup	p.Tyr35Ter	stop_gained, frameshift_variant	2/14	1	NM_000108.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250616 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460860 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E3 deficiency Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 10, 2020	Variant summary: DLD c.104dupA (p.Tyr35X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 250616 control chromosomes (gnomAD). c.104dupA has been reported in the literature in individuals (in compound heterozygous state) affected with Dihydrolipoamide Dehydrogenase Deficiency (MSUD Type 3) (Hong_1996, Shaag_1999). These data indicate that the variant may be associated with disease. Biochemical studies report this variant effect results in decreasing normal activity (Hong_1996, Shaag_1999). One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_000108.3(DLD):c.104dupA(Y35*) is classified as pathogenic in the context of dihydrolipoamide dehydrogenase deficiency. Sources cited for classification include the following: PMID 9298831 and 8968745. Classification of NM_000108.3(DLD):c.104dupA(Y35*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	This sequence change creates a premature translational stop signal (p.Tyr35*) in the DLD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DLD are known to be pathogenic (PMID: 8968745, 9934985). This variant is present in population databases (rs753234219, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with dihydrolipoamide dehydrogenase deficiency (PMID: 8968745, 9934985). ClinVar contains an entry for this variant (Variation ID: 370072). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18362926, 25356417, 8968745, 20672374, 9934985, 15712224, 7815230, 23995961, 9298831) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	DLD: PVS1, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs753234219; hg19: chr7-107533708;