ClinVar Genomic variation as it relates to human health
NM_001079866.2(BCS1L):c.133C>T (p.Arg45Cys)
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.133C>T (p.Arg45Cys)
Variation ID: 6168 Accession: VCV000006168.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 218661120 (GRCh38) [ NCBI UCSC ] 2: 219525843 (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 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001079866.2:c.133C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073335.1:p.Arg45Cys missense NM_001257342.2:c.133C>T NP_001244271.1:p.Arg45Cys missense NM_001257343.2:c.133C>T NP_001244272.1:p.Arg45Cys missense NM_001257344.2:c.133C>T NP_001244273.1:p.Arg45Cys missense NM_001318836.2:c.-40-286C>T intron variant NM_001320717.2:c.133C>T NP_001307646.1:p.Arg45Cys missense NM_001371443.1:c.133C>T NP_001358372.1:p.Arg45Cys missense NM_001371444.1:c.133C>T NP_001358373.1:p.Arg45Cys missense NM_001371446.1:c.133C>T NP_001358375.1:p.Arg45Cys missense NM_001371447.1:c.133C>T NP_001358376.1:p.Arg45Cys missense NM_001371448.1:c.133C>T NP_001358377.1:p.Arg45Cys missense NM_001371449.1:c.133C>T NP_001358378.1:p.Arg45Cys missense NM_001371450.1:c.133C>T NP_001358379.1:p.Arg45Cys missense NM_001371451.1:c.-40-286C>T intron variant NM_001371452.1:c.-41-639C>T intron variant NM_001371453.1:c.-344C>T 5 prime UTR NM_001371454.1:c.-344C>T 5 prime UTR NM_001371455.1:c.-344C>T 5 prime UTR NM_001371456.1:c.-344C>T 5 prime UTR NM_001374085.1:c.133C>T NP_001361014.1:p.Arg45Cys missense NM_001374086.1:c.-344C>T 5 prime UTR NM_004328.5:c.133C>T NP_004319.1:p.Arg45Cys missense NR_163955.1:n.1145C>T non-coding transcript variant NC_000002.12:g.218661120C>T NC_000002.11:g.219525843C>T NG_008018.1:g.6465C>T NG_033099.1:g.3421G>A LRG_539:g.6465C>T Q9Y276:p.Arg45Cys - Protein change
- R45C
- Other names
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- Canonical SPDI
- NC_000002.12:218661119: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) 0.00001
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 | 519 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Jun 1, 2009 | RCV000006543.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV001851700.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 27, 2023 | RCV003472988.1 |
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
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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
(Aug 27, 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: SCV004210798.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 25, 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: SCV002240635.3
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 45 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 45 of the BCS1L protein (p.Arg45Cys). This variant is present in population databases (rs121908575, gnomAD 0.004%). This missense change has been observed in individual(s) with mitochondrial complex III deficiency (PMID: 12910490). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6168). 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%. This variant disrupts the p.Arg45 amino acid residue in BCS1L. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28322498). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2009)
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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: SCV000026726.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 27, 2014 |
Comment on evidence:
In 2 Spanish sibs with fatal infantile complex III deficiency (MC3DN1; 124000), De Meirleir et al. (2003) identified compound heterozygosity for mutation in the BCS1L … (more)
In 2 Spanish sibs with fatal infantile complex III deficiency (MC3DN1; 124000), De Meirleir et al. (2003) identified compound heterozygosity for mutation in the BCS1L gene: a 246C-T transition in exon 1, resulting in an arg45-to-cys (R45C) substitution, and a 279C-T transition in exon 1, resulting in an arg56-to-ter (R56X; 603647.0007) substitution. The R45C substitution occurs in a crucial targeting signal of the gene and is predicted to interfere with proper protein functioning. Each parent was heterozygous for 1 of the mutations. Both patients had severe metabolic acidosis noted shortly after birth, as well as severe liver dysfunction and a renal tubulopathy. One died at age 3 weeks of lactic acidosis. The second infant also had obvious neurologic involvement, with delayed myelination, axial hypotonia, and developmental delay. He died at age 3 months. Postmortem liver examination of both infants showed liver fibrosis, severe cholestasis, and hepatosiderosis with accumulation of iron in aggregates of macrophages and in Kupffer cells. Mitochondria appeared enlarged with few or no cristae and a fluffy matrix. De Meirleir et al. (2003) suggested that the iron accumulation could be explained by the lack of incorporation of iron in the iron-sulfur cluster of complex III. Ramos-Arroyo et al. (2009) reported another Spanish infant with the R45C and R56X mutations. She presented with neonatal severe hypotonia, food intolerance, and vomiting. She soon developed a proximal renal tubulopathy with glucosuria, phosphaturia, and aminoaciduria, metabolic lactic acidosis, and hepatic involvement. Bilateral cataracts were also noted. At age 4 months, she showed nystagmus, hypertonia, microcephaly, developmental delay, and failure to thrive. Her neurologic condition and metabolic acidosis worsened rapidly, and she died at 6 months of age. Biochemical studies of muscle tissue showed impaired activity of mitochondrial complex III. Ramos-Arroyo et al. (2009) noted that this child did not have evidence of altered iron metabolism, as had been observed in the patients reported by De Meirleir et al. (2003), and as has been observed in patients with the allelic disorder GRACILE syndrome (603358). Ramos-Arroyo et al. (2009) postulated that phenotypic variability even in individuals with the same BCS1L genotype may reflect tissue-specific expression of the mutant gene. (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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Novel compound heterozygous mutations in BCS1L gene causing Bjornstad syndrome in two siblings. | Falco M | American journal of medical genetics. Part A | 2017 | PMID: 28322498 |
Clinical and biochemical spectrum of mitochondrial complex III deficiency caused by mutations in the BCS1L gene. | Ramos-Arroyo MA | Clinical genetics | 2009 | PMID: 19508421 |
Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene. | De Meirleir L | American journal of medical genetics. Part A | 2003 | PMID: 12910490 |
Text-mined citations for rs121908575 ...
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.