ClinVar Genomic variation as it relates to human health
NM_001079866.2(BCS1L):c.550C>T (p.Arg184Cys)
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_001079866.2(BCS1L):c.550C>T (p.Arg184Cys)
Variation ID: 6171 Accession: VCV000006171.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 218661848 (GRCh38) [ NCBI UCSC ] 2: 219526571 (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 11, 2015 May 7, 2024 Apr 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001079866.2:c.550C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073335.1:p.Arg184Cys missense NM_001257342.2:c.550C>T NP_001244271.1:p.Arg184Cys missense NM_001257343.2:c.550C>T NP_001244272.1:p.Arg184Cys missense NM_001257344.2:c.550C>T NP_001244273.1:p.Arg184Cys missense NM_001318836.2:c.190C>T NP_001305765.1:p.Arg64Cys missense NM_001320717.2:c.550C>T NP_001307646.1:p.Arg184Cys missense NM_001371443.1:c.550C>T NP_001358372.1:p.Arg184Cys missense NM_001371444.1:c.550C>T NP_001358373.1:p.Arg184Cys missense NM_001371446.1:c.550C>T NP_001358375.1:p.Arg184Cys missense NM_001371447.1:c.550C>T NP_001358376.1:p.Arg184Cys missense NM_001371448.1:c.550C>T NP_001358377.1:p.Arg184Cys missense NM_001371449.1:c.550C>T NP_001358378.1:p.Arg184Cys missense NM_001371450.1:c.550C>T NP_001358379.1:p.Arg184Cys missense NM_001371451.1:c.190C>T NP_001358380.1:p.Arg64Cys missense NM_001371452.1:c.49C>T NP_001358381.1:p.Arg17Cys missense NM_001371453.1:c.49C>T NP_001358382.1:p.Arg17Cys missense NM_001371454.1:c.49C>T NP_001358383.1:p.Arg17Cys missense NM_001371455.1:c.49C>T NP_001358384.1:p.Arg17Cys missense NM_001371456.1:c.49C>T NP_001358385.1:p.Arg17Cys missense NM_001374085.1:c.550C>T NP_001361014.1:p.Arg184Cys missense NM_001374086.1:c.49C>T NP_001361015.1:p.Arg17Cys missense NM_004328.5:c.550C>T NP_004319.1:p.Arg184Cys missense NR_163955.1:n.1562C>T non-coding transcript variant NC_000002.12:g.218661848C>T NC_000002.11:g.219526571C>T NG_008018.1:g.7193C>T NG_033099.1:g.2693G>A LRG_539:g.7193C>T LRG_539t1:c.550C>T LRG_539p1:p.Arg184Cys Q9Y276:p.Arg184Cys - Protein change
- R184C, R64C, R17C
- Other names
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- Canonical SPDI
- NC_000002.12:218661847: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD) 0.00011
Exome Aggregation Consortium (ExAC) 0.00017
The Genome Aggregation Database (gnomAD), exomes 0.00018
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
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. |
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BCS1L | - | - |
GRCh38 GRCh37 |
484 | 520 |
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
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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 (1) |
no assertion criteria provided
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May 15, 2007 | RCV000006546.3 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Apr 24, 2024 | RCV000034811.10 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000384654.14 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Sep 12, 2022 | RCV001142702.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 2, 2023 | RCV003472990.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 15, 2024 | RCV004532300.1 |
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. |
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Likely pathogenic
(Sep 12, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598780.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: BCS1L c.550C>T (p.Arg184Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: BCS1L c.550C>T (p.Arg184Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251364 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in BCS1L causing GRACILE Syndrome (0.00018 vs 0.00047), allowing no conclusion about variant significance. c.550C>T has been reported in the literature in individuals affected with BCS1L-related disorders. These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and showed that this variant caused attenuated growth of yeast train (Hinson_2007, Fernandez-Vizarra_2007). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic n=4, VUS n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Apr 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex III deficiency nuclear type 1
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV000914902.2
First in ClinVar: May 27, 2019 Last updated: May 07, 2024 |
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Likely pathogenic
(Nov 02, 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: SCV000329628.10
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Functional analysis found that the introduction of R184C into yeast with deletion of the BSC1L gene failed to rescue the cell line (Fernandez-Vizarra et al., … (more)
Functional analysis found that the introduction of R184C into yeast with deletion of the BSC1L gene failed to rescue the cell line (Fernandez-Vizarra et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17403714, 19285991, 17314340, 20518024, 22310368, 28322498, Gandelman2020[Case Report], 32375044, 31589614, 23220121, 18620006, 36157077, 33920624, 30582773) (less)
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Pathogenic
(Oct 02, 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: SCV004210782.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 27, 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: SCV002223333.3
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 184 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 184 of the BCS1L protein (p.Arg184Cys). This variant is present in population databases (rs121908578, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with BCS1L-related conditions (PMID: 17314340, 17403714, 30582773). ClinVar contains an entry for this variant (Variation ID: 6171). 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: 17314340, 17403714). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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BCS1L-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004741567.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The BCS1L c.550C>T variant is predicted to result in the amino acid substitution p.Arg184Cys. This variant has been reported in the homozygous and compound heterozygous … (more)
The BCS1L c.550C>T variant is predicted to result in the amino acid substitution p.Arg184Cys. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals affected with Björnstad syndrome/mitochondrial complex III deficiency, and functional studies support its pathogenicity (Hinson et al. 2007. PubMed ID: 17314340; Baker et al. 2019. PubMed ID: 30582773; Fernandez-Vizarra et al. 2007. PubMed ID: 17403714). However it is also documented in more than 40 heterozygous and one homozygous individual of unknown phenotype in the gnomAD database. Based on the collective information, we interpret this change 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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BJORNSTAD SYNDROME WITH MILD MITOCHONDRIAL COMPLEX III DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026729.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In a sporadic case of Bjornstad syndrome (BJS; 262000) with mild mitochondrial complex III deficiency (MC3DN1; 124000), Hinson et al. (2007) found compound heterozygosity for … (more)
In a sporadic case of Bjornstad syndrome (BJS; 262000) with mild mitochondrial complex III deficiency (MC3DN1; 124000), Hinson et al. (2007) found compound heterozygosity for 2 missense mutations in the BCS1L gene: arg184 to cys (R184C) and gly35 to arg (G35R; 603647.0010). In a Moroccan girl with mitochondrial complex III deficiency (124000), Fernandez-Vizarra et al. (2007) identified compound heterozygosity for the R184C mutation and a 547C-T transition in exon 3 of the BCS1L gene, resulting in an arg183-to-cys (R183C; 603647.0012) substitution. She presented at age 9 months with acute psychomotor regression, hypotonia, and failure to thrive, which progressed to spastic quadriparesis and mental retardation associated with abnormal signal intensities in the thalami, basal ganglia, and periventricular white matter, consistent with an encephalopathy. Heart, liver, and kidneys were apparently unaffected, but she was also noted to have brittle hair. Studies in yeast showed that both mutations significantly reduced mitochondrial cytochrome content and respiratory activity, as well as caused a decreased incorporation of the Rieske iron-sulfur protein (UQCRFS1; 191327) into complex III. Further studies showed decreased levels of fully assembled complex III. The findings suggested that BCS1L is necessary for proper complex III assembly. (less)
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Likely pathogenic
(Feb 26, 2016)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802828.1
First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018 |
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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: SCV000058373.3
First in ClinVar: Apr 10, 2013 Last updated: Jan 20, 2017 |
Comment on evidence:
In a sporadic case of Bjornstad syndrome (BJS; 262000) with mild mitochondrial complex III deficiency (MC3DN1; 124000), Hinson et al. (2007) found compound heterozygosity for … (more)
In a sporadic case of Bjornstad syndrome (BJS; 262000) with mild mitochondrial complex III deficiency (MC3DN1; 124000), Hinson et al. (2007) found compound heterozygosity for 2 missense mutations in the BCS1L gene: arg184 to cys (R184C) and gly35 to arg (G35R; 603647.0010). In a Moroccan girl with mitochondrial complex III deficiency (124000), Fernandez-Vizarra et al. (2007) identified compound heterozygosity for the R184C mutation and a 547C-T transition in exon 3 of the BCS1L gene, resulting in an arg183-to-cys (R183C; 603647.0012) substitution. She presented at age 9 months with acute psychomotor regression, hypotonia, and failure to thrive, which progressed to spastic quadriparesis and mental retardation associated with abnormal signal intensities in the thalami, basal ganglia, and periventricular white matter, consistent with an encephalopathy. Heart, liver, and kidneys were apparently unaffected, but she was also noted to have brittle hair. Studies in yeast showed that both mutations significantly reduced mitochondrial cytochrome content and respiratory activity, as well as caused a decreased incorporation of the Rieske iron-sulfur protein (UQCRFS1; 191327) into complex III. Further studies showed decreased levels of fully assembled complex III. The findings suggested that BCS1L is necessary for proper complex III assembly. (less)
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Likely pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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GRACILE syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001455775.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships. | Baker RA | American journal of medical genetics. Part A | 2019 | PMID: 30582773 |
Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease. | Morán M | Biochimica et biophysica acta | 2014 | PMID: 24704045 |
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 rs121908578 ...
HelpRecord last updated May 27, 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.