This sequence change creates a premature translational stop signal (p.Arg285*) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (rs398124598, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 14517957, 24772966, 25333063). ClinVar contains an entry for this variant (Variation ID: 96615). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_183050.4(BCKDHB):c.853C>T (p.Arg285Ter)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic/Likely pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_183050.4(BCKDHB):c.853C>T (p.Arg285Ter)
Variation ID: 96615 Accession: VCV000096615.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6q14.1 6: 80203114 (GRCh38) [ NCBI UCSC ] 6: 80912831 (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 Mar 29, 2015 Jun 17, 2024 Mar 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_183050.4:c.853C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_898871.1:p.Arg285Ter nonsense NM_000056.4:c.853C>T NM_000056.5:c.853C>T NP_000047.1:p.Arg285Ter nonsense NM_001318975.1:c.643C>T NP_001305904.1:p.Arg215Ter nonsense NM_183050.3:c.853C>T NR_134945.2:n.970C>T non-coding transcript variant NC_000006.12:g.80203114C>T NC_000006.11:g.80912831C>T NG_009775.2:g.101488C>T - Protein change
- R285*, R215*
- Other names
- -
- Canonical SPDI
- NC_000006.12:80203113:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD) 0.00015
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00004
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| BCKDHB | - | - |
GRCh38 GRCh37 |
781 | 801 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 16, 2024 | RCV000169304.22 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jan 21, 2019 | RCV001193356.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 23, 2013 | RCV000790747.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 9, 2024 | RCV004566970.1 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 23, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232805.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000952978.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg285*) in the BCKDHB gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg285*) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (rs398124598, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 14517957, 24772966, 25333063). ClinVar contains an entry for this variant (Variation ID: 96615). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease type 1A
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004215946.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jan 21, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease type 1B
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362116.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: The variant, BCKDHB c.853C>T (p.Arg285X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of … (more)
Variant summary: The variant, BCKDHB c.853C>T (p.Arg285X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.5e-05 in 245582 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in BCKDHB causing Maple Syrup Urine Disease Type 1B (4.5e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.853C>T has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease Type 1B (Imtiaz_2017, Bashyam_2012, Quental_2008, Gorzelany_2009, Henneke_2003, Rodriguez-Pombo_2006), which one individual was reported to have <10% normal activity (Rodriguez-Pombo_2006). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease type 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001571371.1
First in ClinVar: Apr 18, 2021 Last updated: Apr 18, 2021 |
Family history: no
Secondary finding: no
|
|
|
Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease type 1A
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002033160.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Likely pathogenic
(Aug 22, 2014)
|
criteria provided, single submitter
Method: literature only
|
Maple syrup urine disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220624.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease type 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal,
paternal,
unknown
|
National Newborn Screening Laboratory, Hospital Nacional de Niños
Accession: SCV002097374.1
First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
Comment:
This is a null variant in a gene where the loss of function is a known disease mechanism, resulting in a truncated protein by creating … (more)
This is a null variant in a gene where the loss of function is a known disease mechanism, resulting in a truncated protein by creating a premature stop codon. This variant is present in population databases in low frequency (gnomAD exomes: 0,00004, ExAC: 0,000008). It has been published in the literature associated with individuals with MSUD (PMID:14517957, 16786533, 34556729). (less)
Observation 1:
Family history: yes
Segregation observed: yes
Observation 2:
Family history: yes
Segregation observed: yes
Observation 3:
Family history: yes
Segregation observed: yes
Observation 4:
Family history: yes
Segregation observed: yes
Observation 5:
Family history: yes
Segregation observed: yes
Observation 6: Observation 7:
Family history: yes
Segregation observed: yes
Observation 8:
Family history: yes
Segregation observed: yes
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease type 1A
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572541.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The homozygous variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000096615/ PMID: 14517957). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Poor suck (present) , Generalized hypotonia (present) , Hyperleucinemia (present)
|
|
|
Pathogenic
(Nov 02, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Maple syrup urine disease type 1B
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002079877.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(Apr 01, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Maple syrup urine disease type 1A
Affected status: yes
Allele origin:
germline
|
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927932.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Variant summary: The variant, BCKDHB c.853C>T (p.Arg285X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.5e-05 in 245582 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in BCKDHB causing Maple Syrup Urine Disease Type 1B (4.5e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.853C>T has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease Type 1B (Imtiaz_2017, Bashyam_2012, Quental_2008, Gorzelany_2009, Henneke_2003, Rodriguez-Pombo_2006), which one individual was reported to have <10% normal activity (Rodriguez-Pombo_2006). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This is a null variant in a gene where the loss of function is a known disease mechanism, resulting in a truncated protein by creating a premature stop codon. This variant is present in population databases in low frequency (gnomAD exomes: 0,00004, ExAC: 0,000008). It has been published in the literature associated with individuals with MSUD (PMID:14517957, 16786533, 34556729).
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The homozygous variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000096615/ PMID: 14517957). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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:
This sequence change creates a premature translational stop signal (p.Arg285*) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (rs398124598, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 14517957, 24772966, 25333063). ClinVar contains an entry for this variant (Variation ID: 96615). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The variant, BCKDHB c.853C>T (p.Arg285X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.5e-05 in 245582 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in BCKDHB causing Maple Syrup Urine Disease Type 1B (4.5e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.853C>T has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease Type 1B (Imtiaz_2017, Bashyam_2012, Quental_2008, Gorzelany_2009, Henneke_2003, Rodriguez-Pombo_2006), which one individual was reported to have <10% normal activity (Rodriguez-Pombo_2006). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This is a null variant in a gene where the loss of function is a known disease mechanism, resulting in a truncated protein by creating a premature stop codon. This variant is present in population databases in low frequency (gnomAD exomes: 0,00004, ExAC: 0,000008). It has been published in the literature associated with individuals with MSUD (PMID:14517957, 16786533, 34556729).
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The homozygous variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000096615/ PMID: 14517957). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease in Chinese Han population. | Fang X | Scientific reports | 2021 | PMID: 34556729 |
| Twenty novel mutations in BCKDHA, BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease. | Imtiaz F | Molecular genetics and metabolism reports | 2017 | PMID: 28417071 |
| Selected reaction monitoring as an effective method for reliable quantification of disease-associated proteins in maple syrup urine disease. | Fernández-Guerra P | Molecular genetics & genomic medicine | 2014 | PMID: 25333063 |
| Analysis of gene mutations among South Indian patients with maple syrup urine disease: identification of four novel mutations. | Narayanan MP | Indian journal of biochemistry & biophysics | 2013 | PMID: 24772966 |
| Molecular genetic analysis of MSUD from India reveals mutations causing altered protein truncation affecting the C-termini of E1α and E1β. | Bashyam MD | Journal of cellular biochemistry | 2012 | PMID: 22593002 |
| Molecular genetics of maple syrup urine disease in the Turkish population. | Gorzelany K | The Turkish journal of pediatrics | 2009 | PMID: 19480318 |
| Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community. | Quental S | Molecular genetics and metabolism | 2008 | PMID: 18378174 |
| Mutational spectrum of maple syrup urine disease in Spain. | Rodríguez-Pombo P | Human mutation | 2006 | PMID: 16786533 |
| Maple syrup urine disease-treatment and outcome in patients of Turkish descent in Germany. | Simon E | The Turkish journal of pediatrics | 2005 | PMID: 15884622 |
| Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease. | Henneke M | Human mutation | 2003 | PMID: 14517957 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BCKDHB | - | - | - | - |
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Text-mined citations for rs398124598 ...
HelpThese 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 Sep 29, 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.