NM_000709.4(BCKDHA):c.1280_1282del (p.Leu427_Ala428delinsPro) AND Maple syrup urine disease

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Sep 20, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000673920.12

Allele description [Variation Report for NM_000709.4(BCKDHA):c.1280_1282del (p.Leu427_Ala428delinsPro)]

NM_000709.4(BCKDHA):c.1280_1282del (p.Leu427_Ala428delinsPro)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_000709.4(BCKDHA):c.1280_1282del (p.Leu427_Ala428delinsPro)

HGVS:

NC_000019.10:g.41424550_41424552del
NG_013004.1:g.31762_31764del
NM_000709.4:c.1280_1282delMANE SELECT
NM_001164783.2:c.1277_1279del
NP_000700.1:p.Leu427_Ala428delinsPro
NP_001158255.1:p.Leu426_Ala427delinsPro
NC_000019.9:g.41930455_41930457del
NM_000709.3:c.1280_1282del
NM_000709.3:c.1280_1282delTGG

Links:

dbSNP: rs755691417

NCBI 1000 Genomes Browser:

rs755691417

Molecular consequence:

NM_000709.4:c.1280_1282del - inframe_indel - [Sequence Ontology: SO:0001820]
NM_001164783.2:c.1277_1279del - inframe_indel - [Sequence Ontology: SO:0001820]

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
SCV000799176	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Apr 11, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001230391	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 20, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21844576, 31980395, 28492532
SCV002032996	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000799176

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Apr 11, 2018)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001230391

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 20, 2022)

germline

clinical testing

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

SCV002032996

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]

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	unknown	unknown	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

Three Korean patients with maple syrup urine disease: four novel mutations in the BCKDHA gene.

Park HD, Lee DH, Hong YH, Kang DH, Lee YK, Song J, Lee SY, Kim JW, Ki CS, Lee YW.

Ann Clin Lab Sci. 2011 Spring;41(2):167-73.

PubMed [citation]

PMID:: 21844576

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 Counsyl, SCV000799176.1

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

From Invitae, SCV001230391.5

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

Description

This variant, c.1280_1282del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the BCKDHA protein (p.Leu427_Ala428delinsPro). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 557742). This variant has been observed in individual(s) with maple syrup urine disease (PMID: 21844576, 31980395; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs755691417, gnomAD 0.006%).

#	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, SCV002032996.1

#	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

Last Updated: Apr 6, 2024

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