ClinVar Genomic variation as it relates to human health
NM_000709.4(BCKDHA):c.793C>T (p.Arg265Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000709.4(BCKDHA):c.793C>T (p.Arg265Trp)
Variation ID: 2379 Accession: VCV000002379.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 41422310 (GRCh38) [ NCBI UCSC ] 19: 41928215 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 23, 2016 Jun 17, 2024 Feb 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000709.4:c.793C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000700.1:p.Arg265Trp missense NM_001164783.2:c.793C>T NP_001158255.1:p.Arg265Trp missense NC_000019.10:g.41422310C>T NC_000019.9:g.41928215C>T NG_013004.1:g.29522C>T - Protein change
- R265W
- Other names
- R220W
- Canonical SPDI
- NC_000019.10:41422309:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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BCKDHA | - | - |
GRCh38 GRCh37 |
736 | 745 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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Sep 12, 2016 | RCV000393620.8 | |
Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 13, 2023 | RCV001379690.14 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 15, 2024 | RCV004566672.1 |
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
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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
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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
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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. |
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Likely pathogenic
(Jun 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Maple syrup urine disease type 1A
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004238500.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 12, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329849.5
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The R265W variant in the BCKDHA gene has previously been reported as R220W in association with maple syrup urine disease (MSUD) (Chuang et al., 1995). … (more)
The R265W variant in the BCKDHA gene has previously been reported as R220W in association with maple syrup urine disease (MSUD) (Chuang et al., 1995). Functional analysis of R265W found that it is associated with no detectable enzyme activity compared to wildtype (Wynn et al., 1998; Wynn et al., 2001). Therefore, we interpret R265W to be a pathogenic variant. (less)
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Likely pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Maple syrup urine disease type 1A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002032907.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Likely pathogenic
(Sep 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Maple syrup urine disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001577535.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg265 amino acid residue in BCKDHA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31112740). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BCKDHA function (PMID: 11069910). 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 BCKDHA protein function. ClinVar contains an entry for this variant (Variation ID: 2379). This variant is also known as R220W. This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 9582350). This variant is present in population databases (rs137852873, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 265 of the BCKDHA protein (p.Arg265Trp). (less)
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Likely pathogenic
(Feb 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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Maple syrup urine disease type 1A
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004215896.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(May 22, 1998)
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no assertion criteria provided
Method: literature only
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MAPLE SYRUP URINE DISEASE, TYPE IA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022636.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In fibroblasts derived a patient with classic maple syrup urine disease (MSUD1A; 248600), Wynn et al. (1998) identified compound heterozygosity for 2 mutations in the … (more)
In fibroblasts derived a patient with classic maple syrup urine disease (MSUD1A; 248600), Wynn et al. (1998) identified compound heterozygosity for 2 mutations in the BCKDHA gene: a C-to-T transition resulting in an arg220-to-trp (R220W) substitution and Y393N (608348.0001). Detailed functional expression studies in E. coli found that the R220W protein showed normal assembly kinetics with the E1-beta subunit and formed a complete tetramer. However, there was no detectable enzyme activity and mildly decreased thermal stability. (less)
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Uncertain significance
(Mar 08, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000706771.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Identification of six novel mutations in five infants with suspected maple syrup urine disease based on blood and urine metabolism screening. | Yang C | Gene | 2019 | PMID: 31112740 |
Roles of active site and novel K+ ion-binding site residues in human mitochondrial branched-chain alpha-ketoacid decarboxylase/dehydrogenase. | Wynn RM | The Journal of biological chemistry | 2001 | PMID: 11069910 |
Impaired assembly of E1 decarboxylase of the branched-chain alpha-ketoacid dehydrogenase complex in type IA maple syrup urine disease. | Wynn RM | The Journal of biological chemistry | 1998 | PMID: 9582350 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BCKDHA | - | - | - | - |
Text-mined citations for rs137852873 ...
HelpRecord last updated Jun 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.