ClinVar Genomic variation as it relates to human health
NM_001079866.2(BCS1L):c.871C>T (p.Arg291Ter)
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.
Pathogenic(5); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001079866.2(BCS1L):c.871C>T (p.Arg291Ter)
Variation ID: 214162 Accession: VCV000214162.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 218662661 (GRCh38) [ NCBI UCSC ] 2: 219527384 (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 May 29, 2016 Jun 17, 2024 Mar 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001079866.2:c.871C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073335.1:p.Arg291Ter nonsense NM_001257342.2:c.871C>T NP_001244271.1:p.Arg291Ter nonsense NM_001257343.2:c.871C>T NP_001244272.1:p.Arg291Ter nonsense NM_001257344.2:c.871C>T NP_001244273.1:p.Arg291Ter nonsense NM_001318836.2:c.511C>T NP_001305765.1:p.Arg171Ter nonsense NM_001320717.2:c.871C>T NP_001307646.1:p.Arg291Ter nonsense NM_001371443.1:c.871C>T NP_001358372.1:p.Arg291Ter nonsense NM_001371444.1:c.871C>T NP_001358373.1:p.Arg291Ter nonsense NM_001371446.1:c.871C>T NP_001358375.1:p.Arg291Ter nonsense NM_001371447.1:c.871C>T NP_001358376.1:p.Arg291Ter nonsense NM_001371448.1:c.871C>T NP_001358377.1:p.Arg291Ter nonsense NM_001371449.1:c.871C>T NP_001358378.1:p.Arg291Ter nonsense NM_001371450.1:c.871C>T NP_001358379.1:p.Arg291Ter nonsense NM_001371451.1:c.511C>T NP_001358380.1:p.Arg171Ter nonsense NM_001371452.1:c.370C>T NP_001358381.1:p.Arg124Ter nonsense NM_001371453.1:c.370C>T NP_001358382.1:p.Arg124Ter nonsense NM_001371454.1:c.370C>T NP_001358383.1:p.Arg124Ter nonsense NM_001371455.1:c.370C>T NP_001358384.1:p.Arg124Ter nonsense NM_001371456.1:c.370C>T NP_001358385.1:p.Arg124Ter nonsense NM_001374085.1:c.871C>T NP_001361014.1:p.Arg291Ter nonsense NM_001374086.1:c.370C>T NP_001361015.1:p.Arg124Ter nonsense NM_004328.5:c.871C>T NP_004319.1:p.Arg291Ter nonsense NR_163955.1:n.1878C>T non-coding transcript variant NC_000002.12:g.218662661C>T NC_000002.11:g.219527384C>T NG_008018.1:g.8006C>T NG_033099.1:g.1880G>A LRG_539:g.8006C>T LRG_539t1:c.871C>T LRG_539p1:p.Arg291Ter - Protein change
- R291*, R171*, R124*
- Other names
- p.R291*:CGA>TGA
- Canonical SPDI
- NC_000002.12:218662660: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 | ||
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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
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. |
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BCS1L | - | - |
GRCh38 GRCh37 |
490 | 528 |
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
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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. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 26, 2023 | RCV000195977.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000368540.5 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 12, 2024 | RCV000586158.9 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2017 | RCV000675151.2 |
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
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. |
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Likely pathogenic
(Apr 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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GRACILE syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800755.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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BCS1L-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000427447.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The BCS1L c.871C>T (p.Arg291Ter) variant is a stop-gained variant. The p.Arg291Ter variant has been reported in one study in which it is found in a … (more)
The BCS1L c.871C>T (p.Arg291Ter) variant is a stop-gained variant. The p.Arg291Ter variant has been reported in one study in which it is found in a compound heterozygous state with a missense variant in one individual with Bjornstad syndrome (Hinson et al. 2007). The p.Arg291Ter variant was absent from 300 control chromosomes and is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional complementation studies in yeast showed that the variant failed to support growth on media that require respiratory-chain metabolism (Hinson et al. 2007). The amount of superoxide produced by complex III activity was reduced by 61% in mitochondria in individuals with Bjornstad syndrome while complex I-dependent production of reactive oxygen species was increased by 30%. Due to the potential impact of stop-gained variants and the supporting evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for BCS1L-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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GRACILE syndrome
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001162936.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Likely pathogenic
(Nov 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pili torti-deafness syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698305.5
First in ClinVar: Mar 17, 2018 Last updated: Dec 24, 2022 |
Comment:
Variant summary: BCS1L c.871C>T (p.Arg291X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BCS1L c.871C>T (p.Arg291X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 250748 control chromosomes (gnomAD). c.871C>T has been reported in the literature in a compound heterozygote individual affected with Bjornstad syndrome (Hinson_2007). The authors of this study also reported experimental evidence evaluating an impact on protein function, demonstrating in a yeast complementation assay that the mutant protein failed to rescue growth on a medium that requires an active respiratory-chain. They also showed decreased electron-transport activities with increased production of reactive oxygen species in lymphocytes acquired from patients with Bjornstad syndrome and complex III deficiency (however, no patient specific data were provided, Hinson_2007). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely pathogenic (n=1) and pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Sep 01, 2022)
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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: SCV000251195.15
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in mitochondrial dysfunction with reduced electron transport chain activity (Hinson et al., 2007); This variant is associated with the following publications: (PMID: 25525159, 29704315, 25914718, 17314340) (less)
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Pathogenic
(Dec 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001231785.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg291*) in the BCS1L gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg291*) in the BCS1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCS1L are known to be pathogenic (PMID: 12215968, 17314340, 19162478, 19508421, 22277166, 25895478). This variant is present in population databases (rs201454788, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Bjornstad syndrome (PMID: 17314340). ClinVar contains an entry for this variant (Variation ID: 214162). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pili torti-deafness syndrome
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503731.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change creates a premature termination codon at position 291 in exon 7 (of 9) of BCS1L, p.(Arg291*). It is expected to result in … (more)
This sequence change creates a premature termination codon at position 291 in exon 7 (of 9) of BCS1L, p.(Arg291*). It is expected to result in an absent or disrupted protein product in a gene where loss of function is an established mechanism of disease. The variant is present in a large population cohort at a frequency of 0.003%, which is consistent with a recessive condition (rs201454788, 8/282,138 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified compound heterozygous with a second allele in a case diagnosed with Bjornstad syndrome (PMID: 17314340). Additionally, the variant demonstrates attenuated growth in a yeast complementation assay (PMID: 17314340). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2, PS3_Supporting. (less)
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Pathogenic
(Mar 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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Pili torti-deafness syndrome
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004210781.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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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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Exome sequencing reveals novel BCS1L mutations in siblings with hearing loss and hypotrichosis. | Zhang J | Gene | 2015 | PMID: 25895478 |
BCS1L gene mutation presenting with GRACILE-like syndrome and complex III deficiency. | Lynn AM | Annals of clinical biochemistry | 2012 | PMID: 22277166 |
Clinical and biochemical spectrum of mitochondrial complex III deficiency caused by mutations in the BCS1L gene. | Ramos-Arroyo MA | Clinical genetics | 2009 | PMID: 19508421 |
Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient. | Blázquez A | Neuromuscular disorders : NMD | 2009 | PMID: 19162478 |
Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. | Hinson JT | The New England journal of medicine | 2007 | PMID: 17314340 |
GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. | Visapää I | American journal of human genetics | 2002 | PMID: 12215968 |
Text-mined citations for rs201454788 ...
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.