rs1554396895

chr7-107893264-AC-A

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.105del(p.Tyr35Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely 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)
• Consequence: DLD NM_000108.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.706

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 7-107893264-AC-A is Pathogenic according to our data. Variant chr7-107893264-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553084.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.105del	p.Tyr35Ter	frameshift_variant	2/14	ENST00000205402.10
DLD	NM_001289751.1	c.105del	p.Tyr35Ter	frameshift_variant	2/13
DLD	NM_001289752.1	c.105del	p.Tyr35Ter	frameshift_variant	2/13
DLD	NM_001289750.1	c.-44del		5_prime_UTR_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLD	ENST00000205402.10	c.105del	p.Tyr35Ter	frameshift_variant	2/14	1	NM_000108.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E3 deficiency Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dihydrolipoamide dehydrogenase deficiency (PMID: 8968745, 9298831, 9934985). ClinVar contains an entry for this variant (Variation ID: 553084). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1554396895; hg19: chr7-107533709;