The R200X variant in the BCS1L gene has been reported previously, as identified by whole exome sequencing, in the compound heterozygous state, opposite of a BSC1L missense variant, in a teenage male who also harbored a hemizygous NLGN4X variant, although no phenotypic details were available (Posey et al., 2017). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R200X 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). We interpret R200X as a pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_001079866.2(BCS1L):c.598C>T (p.Arg200Ter)
Germline
Classification
Help
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.
(6)
Help
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/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001079866.2(BCS1L):c.598C>T (p.Arg200Ter)
Variation ID: 374395 Accession: VCV000374395.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 219526619 (GRCh37) [ NCBI UCSC ] 2: 218661896 (GRCh38) [ 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 Jan 16, 2017 Jun 17, 2024 Jan 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001079866.2:c.598C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073335.1:p.Arg200Ter nonsense NM_001257342.2:c.598C>T NP_001244271.1:p.Arg200Ter nonsense NM_001257343.2:c.598C>T NP_001244272.1:p.Arg200Ter nonsense NM_001257344.2:c.598C>T NP_001244273.1:p.Arg200Ter nonsense NM_001318836.2:c.238C>T NP_001305765.1:p.Arg80Ter nonsense NM_001320717.2:c.598C>T NP_001307646.1:p.Arg200Ter nonsense NM_001371443.1:c.598C>T NP_001358372.1:p.Arg200Ter nonsense NM_001371444.1:c.598C>T NP_001358373.1:p.Arg200Ter nonsense NM_001371446.1:c.598C>T NP_001358375.1:p.Arg200Ter nonsense NM_001371447.1:c.598C>T NP_001358376.1:p.Arg200Ter nonsense NM_001371448.1:c.598C>T NP_001358377.1:p.Arg200Ter nonsense NM_001371449.1:c.598C>T NP_001358378.1:p.Arg200Ter nonsense NM_001371450.1:c.598C>T NP_001358379.1:p.Arg200Ter nonsense NM_001371451.1:c.238C>T NP_001358380.1:p.Arg80Ter nonsense NM_001371452.1:c.97C>T NP_001358381.1:p.Arg33Ter nonsense NM_001371453.1:c.97C>T NP_001358382.1:p.Arg33Ter nonsense NM_001371454.1:c.97C>T NP_001358383.1:p.Arg33Ter nonsense NM_001371455.1:c.97C>T NP_001358384.1:p.Arg33Ter nonsense NM_001371456.1:c.97C>T NP_001358385.1:p.Arg33Ter nonsense NM_001374085.1:c.598C>T NP_001361014.1:p.Arg200Ter nonsense NM_001374086.1:c.97C>T NP_001361015.1:p.Arg33Ter nonsense NM_004328.5:c.598C>T NP_004319.1:p.Arg200Ter nonsense NR_163955.1:n.1610C>T non-coding transcript variant NC_000002.12:g.218661896C>T NC_000002.11:g.219526619C>T NG_008018.1:g.7241C>T NG_033099.1:g.2645G>A LRG_539:g.7241C>T LRG_539t1:c.598C>T LRG_539p1:p.Arg200Ter - Protein change
- R200*, R80*, R33*
- Other names
- -
- Canonical SPDI
- NC_000002.12:218661895: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
- Links
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 |
492 | 530 | |
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) |
no assertion criteria provided
|
Jan 5, 2018 | RCV000415338.2 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2024 | RCV000497971.6 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2021 | RCV002502446.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 18, 2023 | RCV003476004.2 |
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
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
(Jun 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000590222.3
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Comment:
The R200X variant in the BCS1L gene has been reported previously, as identified by whole exome sequencing, in the compound heterozygous state, opposite of a … (more)
The R200X variant in the BCS1L gene has been reported previously, as identified by whole exome sequencing, in the compound heterozygous state, opposite of a BSC1L missense variant, in a teenage male who also harbored a hemizygous NLGN4X variant, although no phenotypic details were available (Posey et al., 2017). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R200X 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). We interpret R200X as a pathogenic variant. (less)
|
|
|
Likely pathogenic
(Jul 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex III deficiency nuclear type 1
Pili torti-deafness syndrome GRACILE syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002809713.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001583205.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg200*) in the BCS1L gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg200*) in the BCS1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCS1L are known to be pathogenic (PMID: 12215968, 17314340, 19162478, 19508421, 22277166, 25895478). This variant is present in population databases (rs776838028, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with BCS1L-related conditions (PMID: 27959697). ClinVar contains an entry for this variant (Variation ID: 374395). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pili torti-deafness syndrome
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004210802.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(May 01, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Mitochondrial complex III deficiency nuclear type 1
(Autosomal recessive inheritance)
Affected status: yes, unknown
Allele origin:
paternal,
germline
|
Baylor Genetics
Accession: SCV000328851.1
First in ClinVar: Jan 16, 2017 Last updated: Jan 16, 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
(Jan 05, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Mitochondrial complex III deficiency nuclear type 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000796961.2
First in ClinVar: Aug 05, 2018 Last updated: Dec 23, 2019 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg200*) in the BCS1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCS1L are known to be pathogenic (PMID: 12215968, 17314340, 19162478, 19508421, 22277166, 25895478). This variant is present in population databases (rs776838028, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with BCS1L-related conditions (PMID: 27959697). ClinVar contains an entry for this variant (Variation ID: 374395). For these reasons, this variant has been classified as Pathogenic.
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, 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.
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. |
Comment:
The R200X variant in the BCS1L gene has been reported previously, as identified by whole exome sequencing, in the compound heterozygous state, opposite of a BSC1L missense variant, in a teenage male who also harbored a hemizygous NLGN4X variant, although no phenotypic details were available (Posey et al., 2017). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R200X 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). We interpret R200X as a pathogenic variant.
Comment:
This sequence change creates a premature translational stop signal (p.Arg200*) in the BCS1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCS1L are known to be pathogenic (PMID: 12215968, 17314340, 19162478, 19508421, 22277166, 25895478). This variant is present in population databases (rs776838028, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with BCS1L-related conditions (PMID: 27959697). ClinVar contains an entry for this variant (Variation ID: 374395). For these reasons, this variant has been classified as Pathogenic.
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, 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. | Posey JE | The New England journal of medicine | 2017 | PMID: 27959697 |
| Exome sequencing reveals novel BCS1L mutations in siblings with hearing loss and hypotrichosis. | Zhang J | Gene | 2015 | PMID: 25895478 |
| BCS1L gene mutation presenting with GRACILE-like syndrome and complex III deficiency. | Lynn AM | Annals of clinical biochemistry | 2012 | PMID: 22277166 |
| Clinical and biochemical spectrum of mitochondrial complex III deficiency caused by mutations in the BCS1L gene. | Ramos-Arroyo MA | Clinical genetics | 2009 | PMID: 19508421 |
| Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient. | Blázquez A | Neuromuscular disorders : NMD | 2009 | PMID: 19162478 |
| Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. | Hinson JT | The New England journal of medicine | 2007 | PMID: 17314340 |
| GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. | Visapää I | American journal of human genetics | 2002 | PMID: 12215968 |
Text-mined citations for rs776838028 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.