NM_183050.4:c.832G>A

Variant names:

• chr6-80201023-G-A
• rs386834233
• NM_183050.4:c.832G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM5 PP2 PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G278D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 9.44
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• maple syrup urine disease type 1B

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P, Myriad Women’s Health
• maple syrup urine disease

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• classic maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intermittent maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thiamine-responsive maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_183050.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-80201024-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3251982.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.17637 (below the threshold of 3.09). Trascript score misZ: -0.0026186 (below the threshold of 3.09). GenCC associations: The gene is linked to classic maple syrup urine disease, thiamine-responsive maple syrup urine disease, intermittent maple syrup urine disease, intermediate maple syrup urine disease, maple syrup urine disease type 1B, maple syrup urine disease.
• PP5: Variant 6-80201023-G-A is Pathogenic according to our data. Variant chr6-80201023-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId 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	c.832G>A	p.Gly278Ser	missense_variant	Exon 7 of 10	ENST00000320393.9	NP_898871.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000579 AC: 88 AN: 151992 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000554 AC: 139 AN: 250872 AF XY: 0.000516

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 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.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 195 AN XY: 724742

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.000179 AC: 8 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.000920 AC: 24 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00262 AC: 140 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000181 AC: 200 AN: 1106856

Other (OTH) AF: 0.000233 AC: 14 AN: 60162

GnomAD4 genome AF: 0.000579 AC: 88 AN: 151992 Hom.: 0 Cov.: 32 AF XY: 0.000754 AC XY: 56 AN XY: 74222

African (AFR) AF: 0.00 AC: 0 AN: 41382

American (AMR) AF: 0.000721 AC: 11 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00388 AC: 41 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000283

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000478 AC: 58

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:7 Other:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2021

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

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). -

-

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: 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. -

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.‚Äã -

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. -

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:4

Aug 31, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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:4

Mar 05, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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) -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 -

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	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		9.4
PrimateAI	Uncertain	0.77	T
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	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.94
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386834233; hg19: chr6-80910740;