rs386834233

Variant names:

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 9.44

Variant links:

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]

BCKDHB links:

Genome browser will be placed here

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 rank	MANE	Protein	UniProt
BCKDHB	NM_183050.4 link	c.832G>A	p.Gly278Ser	missense_variant	Exon 7 of 10	ENST00000320393.9	NP_898871.1	P21953-1A0A140VKB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHB	ENST00000320393.9 link	c.832G>A	p.Gly278Ser	missense_variant	Exon 7 of 10	1	NM_183050.4	ENSP00000318351.5		P21953-1
BCKDHB	ENST00000356489.9 link	c.832G>A	p.Gly278Ser	missense_variant	Exon 7 of 11	1		ENSP00000348880.5		P21953-1

Frequencies

GnomAD3 genomes

AF:

0.000579

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00388

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000554

AC:

139

AN:

250872

Hom.:

AF XY:

0.000516

AC XY:

AN XY:

135566

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00310

Gnomad NFE exome

AF:

0.000388

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000265

AC:

386

AN:

1455988

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

195

AN XY:

724742

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000920

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00262

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.000233

GnomAD4 genome

AF:

0.000579

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.000754

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000721

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00388

Gnomad4 NFE

AF:

0.000471

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000376

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000478

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000178

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

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence 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 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. -

Oct 18, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£ -

Mar 16, 2021

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported in multiple individuals with maple syrup urine disease (MSUD) (PMID: 11509994â€š 14517957â€š 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. -

National Newborn Screening Laboratory, Hospital Nacional de Niños

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Feb 17, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maple syrup urine disease type 1B

Pathogenic:3

Jun 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided

Pathogenic:3

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BCKDHB: PM3:Very Strong, PM2, PP4:Moderate, PP3 -

Sep 08, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 05, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BCKDHB-related disorder

Pathogenic:1

May 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 16, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;D

M_CAP

Pathogenic

0.58

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.98

MVP

0.99

MPC

0.76

ClinPred

0.21

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.94

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over