NM_000709.4(BCKDHA):c.288+9C>T AND Maple syrup urine disease

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 9, 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:: RCV000175638.22

Allele description [Variation Report for NM_000709.4(BCKDHA):c.288+9C>T]

NM_000709.4(BCKDHA):c.288+9C>T

Gene:

BCKDHA:branched chain keto acid dehydrogenase E1 subunit alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_000709.4(BCKDHA):c.288+9C>T

HGVS:

NC_000019.10:g.41410825C>T
NG_013004.1:g.18037C>T
NM_000709.4:c.288+9C>TMANE SELECT
NM_001164783.2:c.288+9C>T
NC_000019.9:g.41916730C>T
NM_000709.3:c.288+9C>T

Links:

dbSNP: rs398123497

NCBI 1000 Genomes Browser:

rs398123497

Molecular consequence:

NM_000709.4:c.288+9C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001164783.2:c.288+9C>T - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000945578	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20431954, 28492532
SCV002033695	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002766092	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 15, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31980395, 20431954 Citation Link,
SCV003823412	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 28, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

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

Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes.

Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, et al.

Mol Genet Metab. 2020 Mar;129(3):193-206. doi: 10.1016/j.ymgme.2020.01.006. Epub 2020 Jan 16.

PubMed [citation]

PMID:: 31980395

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000945578.6

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

Description

This sequence change falls in intron 2 of the BCKDHA gene. It does not directly change the encoded amino acid sequence of the BCKDHA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs398123497, gnomAD 0.02%). This variant has been observed in individual(s) with maple syrup urine disease (PMID: 20431954). 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: 93352). Studies have shown that this variant results in an insertion of 7bp after exon 2 and introduces a premature termination codon (PMID: 20431954). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 Genome-Nilou Lab, SCV002033695.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002766092.1

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

Description

Variant summary: BCKDHA c.288+9C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Some computational tools predict a significant impact on normal splicing: Two predict the variant creates a canonical 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in an alternate transcript with a 7 nt insertion (Fernandez-Guerra_2010). The variant allele was found at a frequency of 5.2e-05 in 251128 control chromosomes. c.288+9C>T has been reported in the literature in individuals affected with Maple Syrup Urine Disease (Fernandez-Guerra_2010, Strauss_2020), and these individuals are reported as compound heterozygous, carrying other pathogenic/likely pathogenic variants. These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One classified it as uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely 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 Revvity Omics, Revvity, SCV003823412.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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