ClinVar Genomic variation as it relates to human health
NM_022437.3(ABCG8):c.1234C>T (p.Arg412Ter)
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_022437.3(ABCG8):c.1234C>T (p.Arg412Ter)
Variation ID: 4972 Accession: VCV000004972.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 43873809 (GRCh38) [ NCBI UCSC ] 2: 44100948 (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 4, 2013 Mar 16, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022437.3:c.1234C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071882.1:p.Arg412Ter nonsense NM_001357321.2:c.1231C>T NP_001344250.1:p.Arg411Ter nonsense NC_000002.12:g.43873809C>T NC_000002.11:g.44100948C>T NG_008884.2:g.46868C>T LRG_1182:g.46868C>T LRG_1182t1:c.1234C>T LRG_1182p1:p.Arg412Ter - Protein change
- R412*, R411*
- Other names
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- Canonical SPDI
- NC_000002.12:43873808: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00011
The Genome Aggregation Database (gnomAD) 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00017
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
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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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ABCG8 | - | - |
GRCh38 GRCh37 |
663 | 731 |
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 (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000005260.12 | |
Pathogenic (2) |
criteria provided, single submitter
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Sep 7, 2022 | RCV000993691.6 | |
Pathogenic (3) |
criteria provided, single submitter
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Nov 13, 2023 | RCV001699176.6 | |
Pathogenic (1) |
criteria provided, single submitter
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May 22, 2023 | RCV003298028.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 19, 2024 | RCV003952343.1 |
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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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Sitosterolemia 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000430523.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The ABCG8 c.1234C>T (p.Arg412Ter) is a stop-gained variant that has been reported in four studies in which it is found in a total of five … (more)
The ABCG8 c.1234C>T (p.Arg412Ter) is a stop-gained variant that has been reported in four studies in which it is found in a total of five individuals with sitosterolemia, all in a compound heterozygous state (Berge et al. 2000; Lu et al. 2001; Lee et al. 2001; Heimerl et al. 2002). The p.Arg412Ter variant was absent from 592 control alleles but is reported at a frequency of 0.00026 in the Latino population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants, the p.Arg412Ter variant is classified as pathogenic for sitosterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Sep 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Sitosterolemia 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003808327.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 13, 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: SCV002227691.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg412*) in the ABCG8 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg412*) in the ABCG8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCG8 are known to be pathogenic (PMID: 11452359, 15375183, 16029460). This variant is present in population databases (rs137852991, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of ABCG8-related conditions (PMID: 11099417, 32088153). ClinVar contains an entry for this variant (Variation ID: 4972). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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ABCG8-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004781146.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The ABCG8 c.1234C>T variant is predicted to result in premature protein termination (p.Arg412*). This variant has been reported in individuals with sitosterolaemia (Berge et al. … (more)
The ABCG8 c.1234C>T variant is predicted to result in premature protein termination (p.Arg412*). This variant has been reported in individuals with sitosterolaemia (Berge et al. 2000. PubMed ID: 11099417; Heimerl et al. 2002. PubMed ID: 12124998). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in ABCG8 are expected to be pathogenic. This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(May 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003998802.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
The p.R412* pathogenic mutation (also known as c.1234C>T), located in coding exon 9 of the ABCG8 gene, results from a C to T substitution at … (more)
The p.R412* pathogenic mutation (also known as c.1234C>T), located in coding exon 9 of the ABCG8 gene, results from a C to T substitution at nucleotide position 1234. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been reported as compound heterozygous with additional alterations in ABCG8 in individuals with sitosterolemia (Berge KE et al. Science, 2000 Dec;290:1771-5; Lee MH et al. Curr Opin Lipidol, 2001 Apr;12:141-9; Lu K et al. Am J Hum Genet, 2001 Aug;69:278-90; Heimerl S et al. Hum Mutat, 2002 Aug;20:151; Xia Y et al. J Clin Lipidol, 2022 Dec;16:40-51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Dec 01, 2000)
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no assertion criteria provided
Method: literature only
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SITOSTEROLEMIA 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025438.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 21, 2019 |
Comment on evidence:
In a Caucasian American child with sitosterolemia (STSL1; 210250), Berge et al. (2000) identified a C-to-T transition at nucleotide 1234 of the ABCG8 gene, resulting … (more)
In a Caucasian American child with sitosterolemia (STSL1; 210250), Berge et al. (2000) identified a C-to-T transition at nucleotide 1234 of the ABCG8 gene, resulting in an arg412-to-ter substitution. The child was a compound heterozygote for the W361X mutation (605460.0001). The child's cholesterol fell from 375 to 201 mg/dl on a low cholesterol diet. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001923662.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973148.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 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, genetic profile and therapy evaluation of 55 children and 5 adults with sitosterolemia. | Xia Y | Journal of clinical lipidology | 2022 | PMID: 34969652 |
ABCG5 and ABCG8 genetic variants in familial hypercholesterolemia. | Reeskamp LF | Journal of clinical lipidology | 2020 | PMID: 32088153 |
Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. | Rees DC | British journal of haematology | 2005 | PMID: 16029460 |
Phenotypic heterogeneity of sitosterolemia. | Wang J | Journal of lipid research | 2004 | PMID: 15375183 |
Mutations in the human ATP-binding cassette transporters ABCG5 and ABCG8 in sitosterolemia. | Heimerl S | Human mutation | 2002 | PMID: 12124998 |
Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. | Lu K | American journal of human genetics | 2001 | PMID: 11452359 |
Genetic basis of sitosterolemia. | Lee MH | Current opinion in lipidology | 2001 | PMID: 11264985 |
Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. | Berge KE | Science (New York, N.Y.) | 2000 | PMID: 11099417 |
Text-mined citations for rs137852991 ...
HelpRecord last updated Mar 17, 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.