ClinVar Genomic variation as it relates to human health
NM_001079866.2(BCS1L):c.547C>T (p.Arg183Cys)
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(1); Likely pathogenic(3); 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.547C>T (p.Arg183Cys)
Variation ID: 6174 Accession: VCV000006174.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 218661845 (GRCh38) [ NCBI UCSC ] 2: 219526568 (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 Sep 14, 2015 Feb 14, 2024 Jan 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001079866.2:c.547C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073335.1:p.Arg183Cys missense NM_001257342.2:c.547C>T NP_001244271.1:p.Arg183Cys missense NM_001257343.2:c.547C>T NP_001244272.1:p.Arg183Cys missense NM_001257344.2:c.547C>T NP_001244273.1:p.Arg183Cys missense NM_001318836.2:c.187C>T NP_001305765.1:p.Arg63Cys missense NM_001320717.2:c.547C>T NP_001307646.1:p.Arg183Cys missense NM_001371443.1:c.547C>T NP_001358372.1:p.Arg183Cys missense NM_001371444.1:c.547C>T NP_001358373.1:p.Arg183Cys missense NM_001371446.1:c.547C>T NP_001358375.1:p.Arg183Cys missense NM_001371447.1:c.547C>T NP_001358376.1:p.Arg183Cys missense NM_001371448.1:c.547C>T NP_001358377.1:p.Arg183Cys missense NM_001371449.1:c.547C>T NP_001358378.1:p.Arg183Cys missense NM_001371450.1:c.547C>T NP_001358379.1:p.Arg183Cys missense NM_001371451.1:c.187C>T NP_001358380.1:p.Arg63Cys missense NM_001371452.1:c.46C>T NP_001358381.1:p.Arg16Cys missense NM_001371453.1:c.46C>T NP_001358382.1:p.Arg16Cys missense NM_001371454.1:c.46C>T NP_001358383.1:p.Arg16Cys missense NM_001371455.1:c.46C>T NP_001358384.1:p.Arg16Cys missense NM_001371456.1:c.46C>T NP_001358385.1:p.Arg16Cys missense NM_001374085.1:c.547C>T NP_001361014.1:p.Arg183Cys missense NM_001374086.1:c.46C>T NP_001361015.1:p.Arg16Cys missense NM_004328.5:c.547C>T NP_004319.1:p.Arg183Cys missense NR_163955.1:n.1559C>T non-coding transcript variant NC_000002.12:g.218661845C>T NC_000002.11:g.219526568C>T NG_008018.1:g.7190C>T NG_033099.1:g.2696G>A LRG_539:g.7190C>T LRG_539t1:c.547C>T LRG_539p1:p.Arg183Cys Q9Y276:p.Arg183Cys - Protein change
- R183C, R63C, R16C
- Other names
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- Canonical SPDI
- NC_000002.12:218661844: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 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 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 |
484 | 519 |
Conditions - Germline
Condition
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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. |
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Likely pathogenic (2) |
criteria provided, single submitter
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Dec 15, 2014 | RCV000006550.9 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2024 | RCV000521027.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 24, 2018 | RCV000674245.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 1, 2023 | RCV003472991.1 |
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
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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
(Dec 15, 2014)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex III deficiency
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Study: CSER-MedSeq
Accession: SCV000245582.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015 |
Comment:
The p.Arg183Cys variant in BCS1L has been identified in 1 compound heterozygous individual with Mitochondrial complex III deficiency (Fernandez-Vizarra 2007). The p.Arg183Cys variant has been … (more)
The p.Arg183Cys variant in BCS1L has been identified in 1 compound heterozygous individual with Mitochondrial complex III deficiency (Fernandez-Vizarra 2007). The p.Arg183Cys variant has been identified in 0.023% (1/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs144885874). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies suggest that this variant impacts protein function (Fernandez-Vizarra 2007). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg183Cys variant is likely pathogenic. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Apr 24, 2018)
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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: SCV000799548.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Oct 30, 2018)
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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: SCV000617286.2
First in ClinVar: Dec 19, 2017 Last updated: Apr 17, 2019 |
Comment:
The R183C pathogenic variant in the BCS1L gene has been reported previously in combination with another BCS1L variant in an individual with early-onset encephalopathy and … (more)
The R183C pathogenic variant in the BCS1L gene has been reported previously in combination with another BCS1L variant in an individual with early-onset encephalopathy and complex III deficiency (Fernandez-Vizarra et al., 2007). The R183C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R183C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional analysis found that the introduction of R183C into yeast with deletion of the BSC1L gene failed to rescue the cell line (Fernandez-Vizarra et al., 2007). We interpret R183C as a pathogenic variant. (less)
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Likely pathogenic
(Oct 01, 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:
unknown
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Baylor Genetics
Accession: SCV004210785.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Jan 04, 2024)
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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: SCV002265125.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 183 of the BCS1L protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 183 of the BCS1L protein (p.Arg183Cys). This variant is present in population databases (rs144885874, gnomAD 0.008%). This missense change has been observed in individual(s) with Bjv?rnstad syndrome (PMID: 17403714). ClinVar contains an entry for this variant (Variation ID: 6174). 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 BCS1L protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BCS1L function (PMID: 17403714). This variant disrupts the p.Arg183 amino acid residue in BCS1L. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17314340). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. (less)
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Pathogenic
(May 15, 2007)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026733.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 23, 2017 |
Comment on evidence:
For discussion of the arg183-to-cys (R183C) mutation in the BCS1L gene that was found in compound heterozygous state in a girl with mitochondrial complex III … (more)
For discussion of the arg183-to-cys (R183C) mutation in the BCS1L gene that was found in compound heterozygous state in a girl with mitochondrial complex III deficiency (MC3DN1; 124000) by Fernandez-Vizarra et al. (2007), see 603647.0009 (less)
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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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Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. | Fernandez-Vizarra E | Human molecular genetics | 2007 | PMID: 17403714 |
Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. | Hinson JT | The New England journal of medicine | 2007 | PMID: 17314340 |
Text-mined citations for rs144885874 ...
HelpRecord last updated Feb 20, 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.