6-80168945-G-C

Variant names:

• chr6-80168945-G-C
• rs79761867
• NM_183050.4:c.548G>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_183050.4(BCKDHB):​c.548G>C​(p.Arg183Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,956 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. R183G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:2
• Conservation: PhyloP100: 9.49
• Publications: 23 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 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_183050.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-80168944-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3335960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 6-80168945-G-C is Pathogenic according to our data. Variant chr6-80168945-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183050.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	NM_183050.4	MANE Select	c.548G>C	p.Arg183Pro	missense	Exon 5 of 10	NP_898871.1
	BCKDHB	NM_001424035.1		c.548G>C	p.Arg183Pro	missense	Exon 5 of 10	NP_001410964.1
	BCKDHB	NM_000056.5		c.548G>C	p.Arg183Pro	missense	Exon 5 of 11	NP_000047.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.548G>C	p.Arg183Pro	missense	Exon 5 of 10	ENSP00000318351.5
	BCKDHB	ENST00000356489.9	TSL:1	c.548G>C	p.Arg183Pro	missense	Exon 5 of 11	ENSP00000348880.5
	BCKDHB	ENST00000369760.8	TSL:3	c.548G>C	p.Arg183Pro	missense	Exon 5 of 6	ENSP00000358775.4

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251348 AF XY: 0.000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000725 AC: 106 AN: 1461840 Hom.: 0 Cov.: 34 AF XY: 0.0000743 AC XY: 54 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111980

Other (OTH) AF: 0.000132 AC: 8 AN: 60392

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:2

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

Jan 01, 2013

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Oct 18, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_183050.2(BCKDHB):c.548G>C(R183P) is classified as likely pathogenic in the context of maple syrup urine disease type Ib and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 11509994, 25255367 and 11448970. Classification of NM_183050.2(BCKDHB):c.548G>C(R183P) 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

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with maple syrup urine disease, type Ib (MIM#248600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated transketolase pyrimidine binding domain (Decipher). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These alternative missense variants p.(Arg183Trp), p.(Arg183Gln) have been previously reported as likely pathogenic, and observed in individuals with maple syrup urine disease (MSUD) (ClinVar, PMID: 28197878). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic, and has been reported in mostly homozygous Ashkenazi Jewish individuals with classic MSUD (ClinVar, PMID: 11509994). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 183 of the BCKDHB protein (p.Arg183Pro). This variant is present in population databases (rs79761867, gnomAD 0.5%). This missense change has been observed in individuals with maple syrup urine disease (PMID: 11509994, 26257134). ClinVar contains an entry for this variant (Variation ID: 11937). 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) 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: 22593002). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_183050.2:c.548G>C in the BCKDHB gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. The BCKDHB c.548G>C (p.Arg183Pro) missense variant has been identified in a total of seven individuals diagnosed with maple syrup urine disease, including five who were homozygous for the variant and two who were compound heterozygous (PMID: 11509994; 21484869). It is a founder mutation in the Ashkenazi Jewish Population. In-silico tools predict a damaging effect of the variant on protein function (PMID: 11509994). Pathogenic computational verdict because 11 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PM3_Strong; PP4; PP3.

Aug 27, 2016

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BCKDHB c.548G>C (p.Arg183Pro) missense variant has been identified in a total of seven individuals diagnosed with maple syrup urine disease, including five who were homozygous for the variant and two who were compound heterozygous (Edelmann et al. 2001; Carecchio et al. 2011). All of these individuals were of Ashkenazi Jewish descent. Edelmann et al. (2001) also identified the variant in a heterozygous state in 9/1014 Ashkenazi Jewish individuals from the New York metro area, indicating a carrier frequency of 1/113 in this population. The p.Arg183Pro variant is reported at a frequency of 0.00047 in the European-American population of the Exome Sequencing Project. The Arg183 residue is conserved. Based on the evidence, the p.Arg183Pro variant is classified as pathogenic for maple syrup urine disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Maple syrup urine disease type 1B Pathogenic:4 Other:1

Oct 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Likely pathogenic and reported on 11-16-2013 by Lab or GTR ID 320494. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Jan 18, 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: BCKDHB c.548G>C affects a conserved nucleotide, resulting in amino acid change from Arg to Pro. 5/5 in-silico tools predict damaging outcome for this variant. This variant is found in 33/123400 control chromosomes at a frequency of 0.0002674, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0014639). The variant has been cited in multiple MSUD patients in homozygous and compound heterozygous state. In addition, at least 1 clinical laboratory classified this variant as pathogenic. Taken together, this is a disease variant and was classified as pathogenic.

Mar 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:3

Jun 02, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 05, 2025

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: 26257134, 28197878, 22593002, 21844576, 11509994, 27175728, 25087612, 27403441, 24268812, 19456321, 23757202, 32151765, 31980395, 31980526, 32778825, 21484869)

Jul 10, 2019

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the BCKDHB gene demonstrated a sequence change, c.548G>C, in exon 5 that results in an amino acid change, p.Arg183Pro. This sequence change has been described in the EXAC database with a low population frequency of 0.02% (dbSNP rs79761867). This pathogenic sequence change has previously been described in patients with maple syrup urine disease (MSUD). The p.Arg183Pro change affects a highly conserved amino acid residue located in a domain of the BCKDHB protein that is known to be functional. The p.Arg183Pro substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This variant is a reported to be a common pathogenic variant in the Ashkenazi Jewish population (PMID: 11509994). Other variants involving this codon have been reported in association with MSUD [OMIM#.248600].

Maple syrup urine disease type 1A Pathogenic:2

Jul 07, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Mar 31, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.548G>C (p.R183P) alteration is located in exon 5 (coding exon 5) of the BCKDHB gene. This alteration results from a G to C substitution at nucleotide position 548, causing the arginine (R) at amino acid position 183 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD) database, the BCKDHB c.548G>C alteration was observed in 0.02% (62/282734) of total alleles studied, with a frequency of 0.53% (55/10368) in the Ashkenazi Jewish subpopulation. This alteration has been reported in the homozygous and compound heterozygous states in patients with maple syrup urine disease and is a common founder mutation in the Ashkenazi Jewish population (Edelmann, 2001; Gupta, 2015). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrate that this alteration affects protein activity and stability in a temperature-dependent manner (Wynn, 2001). The p.R183P alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		9.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		1.0
MPC		0.94
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79761867; hg19: chr6-80878662;