NM_183050.4(BCKDHB):c.348del (p.Asp117fs) AND Maple syrup urine disease

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Nov 6, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000548346.12

Allele description [Variation Report for NM_183050.4(BCKDHB):c.348del (p.Asp117fs)]

NM_183050.4(BCKDHB):c.348del (p.Asp117fs)

Gene:

BCKDHB:branched chain keto acid dehydrogenase E1 subunit beta [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

6q14.1

Genomic location:

Preferred name:

NM_183050.4(BCKDHB):c.348del (p.Asp117fs)

HGVS:

NC_000006.12:g.80167682del
NG_009775.2:g.66056del
NM_000056.5:c.348del
NM_001318975.1:c.138del
NM_183050.4:c.348delMANE SELECT
NP_000047.1:p.Asp117fs
NP_001305904.1:p.Asp47fs
NP_898871.1:p.Asp117fs
NC_000006.11:g.80877396del
NC_000006.11:g.80877399del
NM_000056.4:c.348del
NM_183050.2:c.348del
NM_183050.2:c.348delA
NM_183050.3:c.348del
NR_134945.2:n.371del

Protein change:

D117fs

Links:

dbSNP: rs1400121541

NCBI 1000 Genomes Browser:

rs1400121541

Molecular consequence:

NM_000056.5:c.348del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318975.1:c.138del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_183050.4:c.348del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_134945.2:n.371del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Maple syrup urine disease (MSUD)
Identifiers:: MONDO: MONDO:0009563; MeSH: D008375; MedGen: C0024776; Orphanet: 511; OMIM: PS248600

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Klebsiella pneumoniae strain 1009100, whole genome shotgun sequencing project
Klebsiella pneumoniae strain 1009100, whole genome shotgun sequencing project
gi|1496125467|gb|RDWR00000000.1|RDW 0000

Nucleotide
rhamnogalacturonan lyase [Bacteroides caecimuris]
rhamnogalacturonan lyase [Bacteroides caecimuris]
gi|1180595045|ref|WP_084081195.1|

Protein
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Commission on Professional and Hospital Activities
The non-profit, non-governmental organization which collects, processes, and distributes data on hospital use. Two programs of the Commission are the Professional Activity Stu...<br/>Year introduced: 1991(Aug 1977)

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000627816	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 6, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22593002, 16786533, 26232051, 28492532
SCV001362117	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 16, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16786533, 26232051 Citation Link,
SCV002033142	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003807965	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetic analysis of MSUD from India reveals mutations causing altered protein truncation affecting the C-termini of E1α and E1β.

Bashyam MD, Chaudhary AK, Sinha M, Nagarajaram HA, Devi AR, Bashyam L, Reddy EC, Dalal A.

J Cell Biochem. 2012 Oct;113(10):3122-32. doi: 10.1002/jcb.24189.

PubMed [citation]

PMID:: 22593002

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627816.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Asp117Ilefs*113) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (no rsID available, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 16786533, 26232051). ClinVar contains an entry for this variant (Variation ID: 457148). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362117.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: BCKDHB c.348delA (p.Asp117IlefsX113) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.853C>T, p.Arg285X; c.970C>T, p.Arg324X). The variant allele was found at a frequency of 1.6e-05 in 250924 control chromosomes (gnomAD). c.348delA has been reported in the literature in compound heterozygous and homozygous individuals affected with Maple syrup urine disease (Couce_2015, Rodriguez-Pombo_2006). These data indicate that the variant may be associated with disease. Enzymatic activity in an individual homozygous for the variant was determined to be 14% and in an individual compound heterozygous for the variant and another variant was determined to be 1.3%. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002033142.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807965.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 strong, PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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