rs753234219
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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
Consequence
NM_000108.5 stop_gained, frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
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: 3AN: 250616Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135464
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1460860Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 726644
GnomAD4 genome Cov.: 33
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at