rs398124598
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_183050.4(BCKDHB):c.853C>T(p.Arg285Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,611,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_183050.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHB | NM_183050.4 | c.853C>T | p.Arg285Ter | stop_gained | 8/10 | ENST00000320393.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHB | ENST00000320393.9 | c.853C>T | p.Arg285Ter | stop_gained | 8/10 | 1 | NM_183050.4 | P1 | |
BCKDHB | ENST00000356489.9 | c.853C>T | p.Arg285Ter | stop_gained | 8/11 | 1 | P1 | ||
BCKDHB | ENST00000468520.1 | n.13C>T | non_coding_transcript_exon_variant | 1/3 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 151806Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250734Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135486
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1459224Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 726106
GnomAD4 genome ? AF: 0.000145 AC: 22AN: 151806Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 16AN XY: 74124
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Apr 13, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The homozygous variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000096615/ PMID: 14517957). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 22, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Arg285*) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (rs398124598, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 14517957, 24772966, 25333063). ClinVar contains an entry for this variant (Variation ID: 96615). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | National Newborn Screening Laboratory, Hospital Nacional de Niños | - | This is a null variant in a gene where the loss of function is a known disease mechanism, resulting in a truncated protein by creating a premature stop codon. This variant is present in population databases in low frequency (gnomAD exomes: 0,00004, ExAC: 0,000008). It has been published in the literature associated with individuals with MSUD (PMID:14517957, 16786533, 34556729). - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Maple syrup urine disease type 1B Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 21, 2019 | Variant summary: The variant, BCKDHB c.853C>T (p.Arg285X) 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 4.5e-05 in 245582 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in BCKDHB causing Maple Syrup Urine Disease Type 1B (4.5e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.853C>T has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease Type 1B (Imtiaz_2017, Bashyam_2012, Quental_2008, Gorzelany_2009, Henneke_2003, Rodriguez-Pombo_2006), which one individual was reported to have <10% normal activity (Rodriguez-Pombo_2006). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 02, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 23, 2013 | - - |
Maple syrup urine disease type 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at