NM_000709.4(BCKDHA):c.1312T>A (p.Tyr438Asn) AND Maple syrup urine disease type 1A

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Mar 30, 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:: RCV000002473.17

Allele description [Variation Report for NM_000709.4(BCKDHA):c.1312T>A (p.Tyr438Asn)]

NM_000709.4(BCKDHA):c.1312T>A (p.Tyr438Asn)

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.1312T>A (p.Tyr438Asn)

Other names:

Y393N; p.Y438N:TAC>AAC; NM_001164783.1(BCKDHA):c.1309T>A(p.Tyr437Asn)

HGVS:

NC_000019.10:g.41424582T>A
NG_013004.1:g.31794T>A
NM_000709.4:c.1312T>AMANE SELECT
NM_001164783.2:c.1309T>A
NP_000700.1:p.Tyr438Asn
NP_000700.1:p.Tyr438Asn
NP_001158255.1:p.Tyr437Asn
NC_000019.9:g.41930487T>A
NM_000709.2:c.1312T>A
NM_000709.3:c.1312T>A
NM_001164783.1:c.1309T>A
P12694:p.Tyr438Asn
c.1312T>A (p.Tyr438Asn)

Protein change:

Y437N; TYR393ASN

Links:

Genetic Testing Registry (GTR): GTR000321630; UniProtKB: P12694#VAR_004973; OMIM: 608348.0001; dbSNP: rs137852870

NCBI 1000 Genomes Browser:

rs137852870

Molecular consequence:

NM_000709.4:c.1312T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001164783.2:c.1309T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Maple syrup urine disease type 1A (MSUD1A)
Synonyms:: MSUD type 1A
Identifiers:: MONDO: MONDO:0023691; MedGen: C1855369; OMIM: 248600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000593618	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 5, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000697539	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 6, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14517957, 12888983, 2703538, 14567968 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001461601	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004215880	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	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	yes	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease.

Henneke M, Flaschker N, Helbling C, Müller M, Schadewaldt P, Gärtner J, Wendel U.

Hum Mutat. 2003 Nov;22(5):417.

PubMed [citation]

PMID:: 14517957

Genetic heritage of the Old Order Mennonites of southeastern Pennsylvania.

Puffenberger EG.

Am J Med Genet C Semin Med Genet. 2003 Aug 15;121C(1):18-31.

PubMed [citation]

PMID:: 12888983

See all PubMed Citations (5)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000593618.1

#	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	yes	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, SCV000697539.1

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

Description

Variant summary: The BCKDHA c.1312T>A (p.Tyr438Asn) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this substitution. This variant was found in 6/119260 control chromosomes at a frequency of 0.0000503, which does not exceed the estimated maximal expected allele frequency of a pathogenic BCKDHA variant (0.0016771). It was reported in several MSUD patients in either homozygosity or in compound heterozygosity with other disease causing variants indicating pathogenicity. Moreover, the c.1312T>A is considered to be a founder mutation in certain Mennonite populations (GeneReviews). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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 Natera, Inc., SCV001461601.1

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

#	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 Baylor Genetics, SCV004215880.2

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

Last Updated: Nov 3, 2024

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