ClinVar Genomic variation as it relates to human health
NM_001079866.2(BCS1L):c.205C>T (p.Arg69Cys)
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(4); Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001079866.2(BCS1L):c.205C>T (p.Arg69Cys)
Variation ID: 214160 Accession: VCV000214160.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q35 2: 218661192 (GRCh38) [ NCBI UCSC ] 2: 219525915 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 14, 2024 Jan 9, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001079866.2:c.205C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073335.1:p.Arg69Cys missense NM_001079866.1:c.205C>T NM_001257342.2:c.205C>T NP_001244271.1:p.Arg69Cys missense NM_001257343.2:c.205C>T NP_001244272.1:p.Arg69Cys missense NM_001257344.2:c.205C>T NP_001244273.1:p.Arg69Cys missense NM_001318836.2:c.-40-214C>T intron variant NM_001320717.2:c.205C>T NP_001307646.1:p.Arg69Cys missense NM_001371443.1:c.205C>T NP_001358372.1:p.Arg69Cys missense NM_001371444.1:c.205C>T NP_001358373.1:p.Arg69Cys missense NM_001371446.1:c.205C>T NP_001358375.1:p.Arg69Cys missense NM_001371447.1:c.205C>T NP_001358376.1:p.Arg69Cys missense NM_001371448.1:c.205C>T NP_001358377.1:p.Arg69Cys missense NM_001371449.1:c.205C>T NP_001358378.1:p.Arg69Cys missense NM_001371450.1:c.205C>T NP_001358379.1:p.Arg69Cys missense NM_001371451.1:c.-40-214C>T intron variant NM_001371452.1:c.-41-567C>T intron variant NM_001371453.1:c.-272C>T 5 prime UTR NM_001371454.1:c.-272C>T 5 prime UTR NM_001371455.1:c.-272C>T 5 prime UTR NM_001371456.1:c.-272C>T 5 prime UTR NM_001374085.1:c.205C>T NP_001361014.1:p.Arg69Cys missense NM_001374086.1:c.-272C>T 5 prime UTR NM_004328.5:c.205C>T NP_004319.1:p.Arg69Cys missense NR_163955.1:n.1217C>T non-coding transcript variant NC_000002.12:g.218661192C>T NC_000002.11:g.219525915C>T NG_008018.1:g.6537C>T NG_033099.1:g.3349G>A LRG_539:g.6537C>T LRG_539t1:c.205C>T LRG_539p1:p.Arg69Cys - Protein change
- R69C
- Other names
- p.R69C:CGC>TGC
- Canonical SPDI
- NC_000002.12:218661191:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Exome Aggregation Consortium (ExAC) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00011
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 | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
BCS1L | - | - |
GRCh38 GRCh37 |
484 | 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
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 9, 2024 | RCV000197059.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 4, 2022 | RCV000415034.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 11, 2015 | RCV000623904.9 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2023 | RCV000675122.13 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Nov 1, 2021 | RCV001810436.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 31, 2023 | RCV003474948.1 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex III deficiency nuclear type 1
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518569.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
Uncertain significance
(Nov 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
GRACILE syndrome
Pili torti-deafness syndrome Mitochondrial complex III deficiency nuclear type 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV002060338.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_004328.4(BCS1L):c.205C>T(R69C) is a missense variant classified as a variant of uncertain significance in the context of BCS1L-related disorders. R69C has been observed in cases with … (more)
NM_004328.4(BCS1L):c.205C>T(R69C) is a missense variant classified as a variant of uncertain significance in the context of BCS1L-related disorders. R69C has been observed in cases with relevant disease (PMID: 31435670, 30634555, 27959697). Functional assessments of this variant are available in the literature (PMID: 31435670). R69C has been observed in population frequency databases (gnomAD: FIN 0.03%). In summary, there is insufficient evidence to classify NM_004328.4(BCS1L):c.205C>T(R69C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex III deficiency nuclear type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768359.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bjornstad syndrome (MIM#262000), GRACILE syndrome (MIM#603358) and mitochondrial complex III deficiency, nuclear type (MIM#1124000). Missense variants have been reported to cause all conditions, with clinical severity dependant on the quantity and location of production of reactive oxygen species (PMID: 17314340). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (12 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated import auxiliary sequence (PMID: 31435670). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS, but more commonly and recently as likely pathogenic. It has been reported in several compound heterozygous individuals with Leigh syndrome or aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties (ClinVar, LOVD, PMID: 31435670, PMID: 30634555). An additional individual with mitochondrial complex III deficiency has also been reported, but this individual had an additional hemizygous variant in the NLGN4X gene, which is considered part of a dual molecular diagnosis (PMID: 27959697, ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional analysis of this variant using the muscle biopsy of an affected individual and yeast complementation assays, has demonstrated that this variant has a partial loss of function effect on protein activity.Additionally, it reduced protein expression, mitochondrial respiratory activity and complex III activity (PMID: 31435670). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
Likely pathogenic
(Mar 11, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740812.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Encephalopathy (present) , Aphasia (present) , Cerebellar ataxia (present) , Tics (present) , Tremor (present) , Elevated hepatic transaminases (present) , Elevated serum creatine phosphokinase … (more)
Encephalopathy (present) , Aphasia (present) , Cerebellar ataxia (present) , Tics (present) , Tremor (present) , Elevated hepatic transaminases (present) , Elevated serum creatine phosphokinase (present) , Recurrent streptococcus pneumoniae infections (present) , Deeply set eye (present) , Global developmental delay (present) , Abnormal thalamic MRI signal intensity (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Delayed gross motor development (present) , Delayed speech and language development (present) , Generalized hypotonia (present) , Downturned corners of mouth (present)
Sex: male
Ethnicity/Population group: Caucasian
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
GRACILE syndrome
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV002583278.2
First in ClinVar: Oct 15, 2022 Last updated: Mar 18, 2023 |
|
|
Pathogenic
(Mar 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
GRACILE syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922924.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: BCS1L c.205C>T (p.Arg69Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR014851) of the encoded protein sequence. Five of … (more)
Variant summary: BCS1L c.205C>T (p.Arg69Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR014851) 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 6.8e-05 in 251480 control chromosomes (gnomAD). This frequency is not higher than the estimated maximal expected for a pathogenic variant in BCS1L causing GRACILE Syndrome (0.00047), allowing no conclusion about variant significance. c.205C>T has been reported in the literature in multiple compound heterozygous individuals affected with symptoms that belong to the spectrum of BCS1L-related disorders (Olahova_2019, Hikmat_2021, Jou_2019, Posey_2017), all carrying a (likely) pathogenic variant in trans. These data indicate that the variant is likely to be associated with disease. At least one of these publications also reported experimental evidence, and demonstrated a partial loss of function in patient derived cells and in yeast complementation assays (Olahova_2019). Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=3) / likely pathogenic (n=3) or VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Likely pathogenic
(Apr 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000251193.13
First in ClinVar: Oct 11, 2015 Last updated: Aug 05, 2023 |
Comment:
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: 19508421, … (more)
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: 19508421, 17403714, 17314340, 12215968, 11528392, 31435670, 34662929, 27959697) (less)
|
|
Likely pathogenic
(Aug 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pili torti-deafness syndrome
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004210796.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jan 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001205466.5
First in ClinVar: Apr 15, 2020 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 69 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 69 of the BCS1L protein (p.Arg69Cys). This variant is present in population databases (rs377025174, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of mitochondrial complex III deficiency (PMID: 27959697, 31435670; Invitae). 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: 214160). 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: 31435670). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Uncertain significance
(May 01, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Mitochondrial complex III deficiency nuclear type 1
(Autosomal recessive inheritance)
Affected status: unknown, yes
Allele origin:
maternal,
germline
|
Baylor Genetics
Accession: SCV000328852.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
Comment:
Our laboratory reported dual molecular diagnoses in BCS1L (NM_004328.4:c.598C>T; NM_004328.4:c.205C>T ; in trans) and NLGN4X (NM_181332.1:c.301C>T) in an individual with short stature, failure to thrive, … (more)
Our laboratory reported dual molecular diagnoses in BCS1L (NM_004328.4:c.598C>T; NM_004328.4:c.205C>T ; in trans) and NLGN4X (NM_181332.1:c.301C>T) in an individual with short stature, failure to thrive, rickets, Fanconi syndrome, delayed motor milestones, absent speech, developmental regression, intellectual disability, hypotonia, seizure disorder, gait ataxia, abnormal movements (laughing behavior and tongue protrusion), dysmorphic features, microcephaly, history of seizure disorder. (less)
Observation 1: Observation 2: |
|
Likely pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
GRACILE syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001455774.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Expanding the phenotypic spectrum of BCS1L-related mitochondrial disease. | Hikmat O | Annals of clinical and translational neurology | 2021 | PMID: 34662929 |
Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease. | Oláhová M | Human molecular genetics | 2019 | PMID: 31435670 |
Muscle Involvement in a Large Cohort of Pediatric Patients with Genetic Diagnosis of Mitochondrial Disease. | Jou C | Journal of clinical medicine | 2019 | PMID: 30634555 |
Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships. | Baker RA | American journal of medical genetics. Part A | 2019 | PMID: 30582773 |
Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. | Posey JE | The New England journal of medicine | 2017 | PMID: 27959697 |
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 rs377025174 ...
HelpRecord last updated Apr 15, 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.