rs79761867
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_183050.4(BCKDHB):c.548G>A(p.Arg183Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,840 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_183050.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHB | NM_183050.4 | c.548G>A | p.Arg183Gln | missense_variant | 5/10 | ENST00000320393.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHB | ENST00000320393.9 | c.548G>A | p.Arg183Gln | missense_variant | 5/10 | 1 | NM_183050.4 | P1 | |
BCKDHB | ENST00000356489.9 | c.548G>A | p.Arg183Gln | missense_variant | 5/11 | 1 | P1 | ||
BCKDHB | ENST00000369760.8 | c.548G>A | p.Arg183Gln | missense_variant | 5/6 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251348Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135856
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461840Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727222
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 28, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 183 of the BCKDHB protein (p.Arg183Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with maple-syrup urine disease (PMID: 22593002). ClinVar contains an entry for this variant (Variation ID: 527135). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BCKDHB protein function with a positive predictive value of 80%. This variant disrupts the p.Arg183 amino acid residue in BCKDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11448970, 11509994, 21484869). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Maple syrup urine disease type 1B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 17, 2023 | Variant summary: BCKDHB c.548G>A (p.Arg183Gln) results in a conservative amino acid change located in the Transketolase-like, pyrimidine-binding domain (IPR005475) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251348 control chromosomes. c.548G>A has been reported in the literature as a presumed compound heterozygous genotype (phase not specified) in at-least one individual affected with Maple Syrup Urine Disease (example, Bashyam_2012). A different nucleotide change, namely, c.548G>C (p.Arg183Pro) has also been reported as compound heterozygous genotype in an individual with Maple Syrup Urine Disease (example, Gupta_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22593002, 26257134, 28197878). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at