chr1-100240859-CAT-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001918.5(DBT):c.75_76delAT(p.Cys26TrpfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,208 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. T25T) has been classified as Likely benign.
Frequency
Consequence
NM_001918.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000677 AC: 17AN: 251058Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135698
GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461038Hom.: 0 AF XY: 0.0000454 AC XY: 33AN XY: 726852
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 17, 2024 | Variant summary: DBT c.75_76delAT (p.Cys26TrpfsX2) 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 6.8e-05 in 251058 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DBT causing Maple Syrup Urine Disease (6.8e-05 vs 0.0012), allowing no conclusion about variant significance. c.75_76delAT has been reported in the literature in individuals affected with Maple Syrup Urine Disease (example: Pode-Shakked_2020). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 32151765). ClinVar contains an entry for this variant (Variation ID: 11950). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 16, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 14, 2024 | This sequence change creates a premature translational stop signal (p.Cys26Trpfs*2) in the DBT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DBT are known to be pathogenic (PMID: 16579849, 16786533). This variant is present in population databases (rs768832921, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 8430702, 14517957, 16468966, 20639189, 28417071). ClinVar contains an entry for this variant (Variation ID: 11950). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | NM_001918.3(DBT):c.75_76delAT(C26Wfs*2) is classified as pathogenic in the context of maple syrup urine disease type II. Sources cited for classification include the following: PMID 8430702. Classification of NM_001918.3(DBT):c.75_76delAT(C26Wfs*2) 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 | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Maple syrup urine disease type 2 Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 12, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 23, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 18, 2019 | - - |
Maple syrup urine disease type 1A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Jun 12, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 09, 2024 | Frameshift 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: 24394677, 32193832, 34671977, 32151765, 31980395, 31980526, 31589614, 32712949, 8430702, 16468966, 34556729, 20639189, 16786533, 14517957, 28417071) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at