VCV000093361.41 - ClinVar

NM_000709.4(BCKDHA):c.452C>T (p.Thr151Met)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000709.4(BCKDHA):c.452C>T (p.Thr151Met)

Variation ID: 93361 Accession: VCV000093361.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.2 19: 41414125 (GRCh38) [ NCBI UCSC ] 19: 41920030 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 31, 2016	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000709.4:c.452C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000700.1:p.Thr151Met	missense
NM_001164783.2:c.452C>T	NP_001158255.1:p.Thr151Met	missense
NC_000019.10:g.41414125C>T
NC_000019.9:g.41920030C>T
NG_013004.1:g.21337C>T
	P12694:p.Thr151Met

... more HGVS ... less HGVS

Protein change

T151M

Other names

NM_000709.3(BCKDHA):c.452C>T(p.Thr151Met)
NM_001164783.1(BCKDHA):c.452C>T(p.Thr151Met)

Canonical SPDI

NC_000019.10:41414124:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00419 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00419

1000 Genomes Project 30x 0.00422

Trans-Omics for Precision Medicine (TOPMed) 0.00627

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00753

The Genome Aggregation Database (gnomAD) 0.00790

The Genome Aggregation Database (gnomAD), exomes 0.00976

Exome Aggregation Consortium (ExAC) 0.01078

Links

ClinGen: CA146875 UniProtKB: P12694#VAR_034361 dbSNP: rs34442879 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BCKDHA		-	-	GRCh38 GRCh37	741	751

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	May 31, 2018	RCV000079243.26
Maple syrup urine disease	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000295914.33
Maple syrup urine disease type 1A	Benign (2)	criteria provided, single submitter	Oct 14, 2023	RCV001273305.11
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Nov 1, 2023	RCV001705729.21

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Apr 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000305438.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Dec 18, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Maple syrup urine disease type 1A Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743924.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Benign (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Not specified Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803448.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018	Comment: This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >1% in Exome Aggregation … (more) This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >1% in Exome Aggregation Consortium. BCKDHA mutations are responsible for Maple syrup urine disease but it is not known if this variant has been ever seen in patients. (less)
Benign (Feb 26, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000111113.8 First in ClinVar: Jan 17, 2014 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BCKDHA Number of individuals with the variant: 4 Sex: mixed
Benign (Sep 02, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000296955.3 First in ClinVar: Jul 31, 2016 Last updated: Dec 24, 2022
Benign (Oct 14, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Maple syrup urine disease type 1A Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602630.7 First in ClinVar: Sep 28, 2017 Last updated: Feb 20, 2024
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Maple syrup urine disease type 1A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000413348.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Maple syrup urine disease type 1A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435208.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Comment: The heterozygous p.Thr151Met variant, sometimes called p.Thr106Met due to a difference in cDNA numbering, in BCKDHA has been identified in a Turkish individual with maple … (more) The heterozygous p.Thr151Met variant, sometimes called p.Thr106Met due to a difference in cDNA numbering, in BCKDHA has been identified in a Turkish individual with maple syrup urine disease (PMID: 12118532), but has also been identified in >2% of European (Finnish) chromosomes and 9 homozygotes in ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive maple syrup urine disease. (less) Ethnicity/Population group: Caucasian;Macedonian
Benign (Dec 05, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001881802.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Comment: This variant is associated with the following publications: (PMID: 32193832, 31119508, 26990548, 14517957, 27535533, 27884173, 12118532, 21228398, 20981092, 22995991, 25087612)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Maple syrup urine disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001728176.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005208430.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Nov 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004143826.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: BCKDHA: BS1, BS2 Number of individuals with the variant: 3
Benign (Jun 03, 2020)	no assertion criteria provided Method: clinical testing	Maple syrup urine disease type 1A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001456201.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001926140.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
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Comment:

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >1% in Exome Aggregation Consortium. BCKDHA mutations are responsible for Maple syrup urine disease but it is not known if this variant has been ever seen in patients.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

The heterozygous p.Thr151Met variant, sometimes called p.Thr106Met due to a difference in cDNA numbering, in BCKDHA has been identified in a Turkish individual with maple syrup urine disease (PMID: 12118532), but has also been identified in >2% of European (Finnish) chromosomes and 9 homozygotes in ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive maple syrup urine disease.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BCKDHA	-	-	-	-

Text-mined citations for rs34442879 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000709.4(BCKDHA):c.452C>T (p.Thr151Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs34442879 ...