ClinVar Genomic variation as it relates to human health
NM_001079866.2(BCS1L):c.548G>A (p.Arg183His)
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.548G>A (p.Arg183His)
Variation ID: 6170 Accession: VCV000006170.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 218661846 (GRCh38) [ NCBI UCSC ] 2: 219526569 (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 Apr 27, 2014 Feb 14, 2024 Nov 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001079866.2:c.548G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073335.1:p.Arg183His missense NM_001257342.2:c.548G>A NP_001244271.1:p.Arg183His missense NM_001257343.2:c.548G>A NP_001244272.1:p.Arg183His missense NM_001257344.2:c.548G>A NP_001244273.1:p.Arg183His missense NM_001318836.2:c.188G>A NP_001305765.1:p.Arg63His missense NM_001320717.2:c.548G>A NP_001307646.1:p.Arg183His missense NM_001371443.1:c.548G>A NP_001358372.1:p.Arg183His missense NM_001371444.1:c.548G>A NP_001358373.1:p.Arg183His missense NM_001371446.1:c.548G>A NP_001358375.1:p.Arg183His missense NM_001371447.1:c.548G>A NP_001358376.1:p.Arg183His missense NM_001371448.1:c.548G>A NP_001358377.1:p.Arg183His missense NM_001371449.1:c.548G>A NP_001358378.1:p.Arg183His missense NM_001371450.1:c.548G>A NP_001358379.1:p.Arg183His missense NM_001371451.1:c.188G>A NP_001358380.1:p.Arg63His missense NM_001371452.1:c.47G>A NP_001358381.1:p.Arg16His missense NM_001371453.1:c.47G>A NP_001358382.1:p.Arg16His missense NM_001371454.1:c.47G>A NP_001358383.1:p.Arg16His missense NM_001371455.1:c.47G>A NP_001358384.1:p.Arg16His missense NM_001371456.1:c.47G>A NP_001358385.1:p.Arg16His missense NM_001374085.1:c.548G>A NP_001361014.1:p.Arg183His missense NM_001374086.1:c.47G>A NP_001361015.1:p.Arg16His missense NM_004328.5:c.548G>A NP_004319.1:p.Arg183His missense NR_163955.1:n.1560G>A non-coding transcript variant NC_000002.12:g.218661846G>A NC_000002.11:g.219526569G>A NG_008018.1:g.7191G>A NG_033099.1:g.2695C>T LRG_539:g.7191G>A LRG_539t1:c.548G>A LRG_539p1:p.Arg183His Q9Y276:p.Arg183His - Protein change
- R183H, R63H, R16H
- Other names
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- Canonical SPDI
- NC_000002.12:218661845:G:A
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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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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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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BCS1L | - | - |
GRCh38 GRCh37 |
- | 519 |
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
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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 24, 2023 | RCV000006545.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2018 | RCV000779835.1 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 6, 2021 | RCV001835622.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 19, 2022 | RCV002243624.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 25, 2021 | RCV002476937.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 18, 2023 | RCV002512833.2 |
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
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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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Pathogenic
(Feb 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Leigh syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916675.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: BCS1L c.548G>A (p.Arg183His) results in a non-conservative amino acid change located in the N-terminal BCS1 domain of the encoded protein sequence. Five of … (more)
Variant summary: BCS1L c.548G>A (p.Arg183His) results in a non-conservative amino acid change located in the N-terminal BCS1 domain of 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 1.6e-05 in 246466 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BCS1L causing Bjornstad syndrome (1.6e-05 vs 0.00047), allowing no conclusion about variant significance. The c.548G>A variant has been reported in the literature in a consanguineous family with numerous affected individuals, all of whom were homozygous for the variant, inherited from heterozygous parents (Hinson_2007). These data indicate that the variant is very likely to be associated with disease. The same publication reports experimental complementation assays in yeast that showed a significant effect on protein function, where yeast growth rate was reduced to <10% of normal. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Additionally, a variant affecting the same codon (c.547C>T, p.Arg183Cys) is classified as pathogenic/likely pathogenic by multiple reputable clinical labs via ClinVar, supporting the functional impact of this position. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex III deficiency nuclear type 1
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512446.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 moderate, PP1 moderate, PP3 supporting
Geographic origin: Brazil
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Pathogenic
(Oct 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex III deficiency nuclear type 1
Pili torti-deafness syndrome GRACILE syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002787357.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 24, 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: SCV004210788.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 18, 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: SCV003524977.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 183 of the BCS1L protein (p.Arg183His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 183 of the BCS1L protein (p.Arg183His). This variant is present in population databases (rs121908577, gnomAD 0.007%). This missense change has been observed in individual(s) with Bjv?rnstad syndrome (PMID: 17314340). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6170). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 22, 2007)
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no assertion criteria provided
Method: literature only
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BJORNSTAD SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026728.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 27, 2014 |
Comment on evidence:
In affected members of the family with Bjornstad syndrome (BJS; 262000) in which Lubianca Neto et al. (1998) demonstrated linkage to 2q, Hinson et al. … (more)
In affected members of the family with Bjornstad syndrome (BJS; 262000) in which Lubianca Neto et al. (1998) demonstrated linkage to 2q, Hinson et al. (2007) identified homozygosity for a C-to-T transition in the BCS1L gene, resulting in an arg183-to-his (R183H) substitution. Eight individuals in 2 sibships related as first cousins once removed were affected; the parents in each case were consanguineous. (less)
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Pathogenic
(Jul 06, 2021)
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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: SCV002076351.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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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Nuclear gene mutations as the cause of mitochondrial complex III deficiency. | Fernández-Vizarra E | Frontiers in genetics | 2015 | PMID: 25914718 |
Exome sequencing reveals novel BCS1L mutations in siblings with hearing loss and hypotrichosis. | Zhang J | Gene | 2015 | PMID: 25895478 |
Novel mutation in AAA domain of BCS1L causing Bjornstad syndrome. | Siddiqi S | Journal of human genetics | 2013 | PMID: 24172246 |
Pathogenic mutations in the 5' untranslated region of BCS1L mRNA in mitochondrial complex III deficiency. | Gil-Borlado MC | Mitochondrion | 2009 | PMID: 19389488 |
Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. | Hinson JT | The New England journal of medicine | 2007 | PMID: 17314340 |
The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene maps to chromosome 2q34-36. | Lubianca Neto JF | American journal of human genetics | 1998 | PMID: 9545407 |
Text-mined citations for rs121908577 ...
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.