NM_183050.4(BCKDHB):c.392G>T (p.Gly131Val) AND Maple syrup urine disease

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 5, 2024
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:: RCV001918259.5

Allele description [Variation Report for NM_183050.4(BCKDHB):c.392G>T (p.Gly131Val)]

NM_183050.4(BCKDHB):c.392G>T (p.Gly131Val)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

6q14.1

Genomic location:

Preferred name:

NM_183050.4(BCKDHB):c.392G>T (p.Gly131Val)

HGVS:

NC_000006.12:g.80167726G>T
NG_009775.2:g.66100G>T
NM_000056.5:c.392G>T
NM_001318975.1:c.182G>T
NM_183050.3:c.392G>T
NM_183050.4:c.392G>TMANE SELECT
NP_000047.1:p.Gly131Val
NP_001305904.1:p.Gly61Val
NP_898871.1:p.Gly131Val
NC_000006.11:g.80877443G>T
NM_183050.4:c.392G>T
NR_134945.2:n.415G>T

Protein change:

G131V

Links:

dbSNP: rs774472182

NCBI 1000 Genomes Browser:

rs774472182

Molecular consequence:

NM_000056.5:c.392G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318975.1:c.182G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_183050.4:c.392G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_134945.2:n.415G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

Recent activity

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Acacia mearnsii isolate JM4402 tRNA-Lys (trnK) gene, intron; chloroplast
Acacia mearnsii isolate JM4402 tRNA-Lys (trnK) gene, intron; chloroplast
gi|733388211|gb|KM090626.1|

Nucleotide
Acacia decurrens isolate JM4399 tRNA-Lys (trnK) gene, intron; chloroplast
Acacia decurrens isolate JM4399 tRNA-Lys (trnK) gene, intron; chloroplast
gi|733388208|gb|KM090623.1|

Nucleotide
ALDH3A1 [Phyllostomus discolor]
ALDH3A1 [Phyllostomus discolor]
Gene ID:114515386

Gene
primed_primed_Oct4_RNA_3
primed_primed_Oct4_RNA_3

GEO DataSets

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002179705	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 24, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 29740478, 32193832, 31980395, 33955723, 28492532
SCV005077384	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 5, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31980395, 33131499, 33955723 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002179705

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 24, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV005077384

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 5, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

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

Citations

PubMed

A Novel Whole Gene Deletion of BCKDHB by Alu-Mediated Non-allelic Recombination in a Chinese Patient With Maple Syrup Urine Disease.

Liu G, Ma D, Hu P, Wang W, Luo C, Wang Y, Sun Y, Zhang J, Jiang T, Xu Z.

Front Genet. 2018;9:145. doi: 10.3389/fgene.2018.00145.

PubMed [citation]

PMID:: 29740478
PMCID:: PMC5928131

Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease.

Sun WH, Wu BB, Wang YQ, Wu MY, Dong XR, Zhang YP, Lu W, Zhang P, Yang B, Zhang M, Wu HJ, Zhou WH.

World J Pediatr. 2020 Aug;16(4):401-410. doi: 10.1007/s12519-020-00349-1. Epub 2020 Mar 19.

PubMed [citation]

PMID:: 32193832

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002179705.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly131 amino acid residue in BCKDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29740478, 32193832). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt BCKDHB protein function. ClinVar contains an entry for this variant (Variation ID: 1407094). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 31980395, 33955723). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 131 of the BCKDHB protein (p.Gly131Val).

#	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, SCV005077384.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: BCKDHB c.392G>T (p.Gly131Val) results in a non-conservative amino acid change located in the Transketolase-like, pyrimidine-binding domain (IPR005475) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251182 control chromosomes. c.392G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with classic Maple Syrup Urine Disease (e.g. Strauss_2020, Margutti_2020, Campanholi_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33955723, 33131499, 31980395). ClinVar contains an entry for this variant (Variation ID: 1407094). 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

Last Updated: Sep 29, 2024

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