rs386834233
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_183050.4(BCKDHB):c.832G>A(p.Gly278Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,607,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )
Consequence
BCKDHB
NM_183050.4 missense
NM_183050.4 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 9.44
Genes affected
BCKDHB (HGNC:987): (branched chain keto acid dehydrogenase E1 subunit beta) This gene encodes the E1 beta subunit of branched-chain keto acid dehydrogenase, which is a multienzyme complex associated with the inner membrane of mitochondria. This enzyme complex functions in the catabolism of branched-chain amino acids. Mutations in this gene have been associated with maple syrup urine disease (MSUD), type 1B, a disease characterized by a maple syrup odor to the urine in addition to mental and physical retardation and feeding problems. Alternative splicing at this locus results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-80201023-G-A is Pathogenic according to our data. Variant chr6-80201023-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BCKDHB | NM_183050.4 | c.832G>A | p.Gly278Ser | missense_variant | 7/10 | ENST00000320393.9 | NP_898871.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000579 AC: 88AN: 151992Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000554 AC: 139AN: 250872Hom.: 0 AF XY: 0.000516 AC XY: 70AN XY: 135566
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GnomAD4 exome AF: 0.000265 AC: 386AN: 1455988Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 195AN XY: 724742
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GnomAD4 genome 0.000579 AC: 88AN: 151992Hom.: 0 Cov.: 32 AF XY: 0.000754 AC XY: 56AN XY: 74222
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Maple syrup urine disease Pathogenic:7Other:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 17, 2023 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported in multiple individuals with maple syrup urine disease (MSUD) (PMID: 11509994‚ 14517957‚ 17922217, 14567968, 20307994). The c.832G>A (p.Gly278Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.058% (164/282184). It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.832G>A (p.Gly278Ser) variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Newborn Screening Laboratory, Hospital Nacional de Niños | - | This is a missense variant located within exon 7 and generates a change from the aminoacid Glycine to a Serine in position 278. It is present in population databases in low frequency (GnomAD exomes: 0.00055; ExAc: 0.00048). This variant has been published in the literature associated with individuals with MSUD ( PMID: 11509994, PMID: 14517957, PMID: 17922217). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 278 of the BCKDHB protein (p.Gly278Ser). This variant is present in population databases (rs386834233, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with BCKDHB-related conditions, some of which present with lab findings that are highly specific for maple syrup urine disease (PMID: 11509994, 14567968, 17922217, 20307994). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 65771). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BCKDHB protein function. For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | NM_183050.2(BCKDHB):c.832G>A(G278S) is classified as likely pathogenic in the context of maple syrup urine disease type Ib and is associated with the intermediate form of this disease. Sources cited for classification include the following: PMID 14567968, 17922217 and 20307994. Classification of NM_183050.2(BCKDHB):c.832G>A(G278S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Mar 16, 2021 | - - |
Maple syrup urine disease type 1B Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 08, 2016 | Variant summary: The BCKDHB c.832G>A (p.Gly278Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). The G278S substitution exhibits a shift in polarity from non-polar to polar, and G278 is located in the Transketolase C-terminal/Pyruvate-ferredoxin oxidoreductase domain II of the 2-oxoisovalerate dehydrogenase subunit beta protein. Functional studies in fibroblasts from compound heterozygous patients show enzyme activity of <10%. This variant was found in 58/120788 control chromosomes at a frequency of 0.0004802, which does not exceed the estimated maximal expected allele frequency of a pathogenic BCKDHB variant (0.0014639). G278S has been reported in numerous MSUD patients in the literature in compound heterozygous state. Furthermore, at least one clinical diagnostic laboratory classified this variant as pathogenic, and the variant is reported as a commonly known pathogenic variant in the literature. Taken together, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 21, 2024 | - - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 05, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 23952016, 11509994, 20307994, 17922217, 31980526, 34426522, 33726816, 14517957) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | BCKDHB: PM3:Very Strong, PM2, PP4:Moderate, PP3 - |
BCKDHB-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 03, 2024 | The BCKDHB c.832G>A variant is predicted to result in the amino acid substitution p.Gly278Ser. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with maple syrup urine disease (see for example, Edelmann et al. 2001. PubMed ID: 11509994; Table 2, Flaschker et al. 2007. PubMed ID: 17922217; Puckett et al. 2009. PubMed ID: 20307994). This variant is reported in 0.29% of alleles in individuals of European (Finnish) descent in gnomAD. In vitro experimental studies suggest this variant, in the compound heterozygous state, reduces enzymatic activity (Table 2, Nellis et al. 2003. PubMed ID: 14567968; Table 2, Flaschker et al. 2007. PubMed ID: 17922217). This variant is interpreted as pathogenic. - |
Maple syrup urine disease type 1A Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 16, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
0.76
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at