ClinVar Genomic variation as it relates to human health
NM_020297.4(ABCC9):c.3461G>A (p.Arg1154Gln)
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_020297.4(ABCC9):c.3461G>A (p.Arg1154Gln)
Variation ID: 31947 Accession: VCV000031947.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p12.1 12: 21842326 (GRCh38) [ NCBI UCSC ] 12: 21995260 (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 Feb 20, 2024 Sep 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020297.4:c.3461G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_064693.2:p.Arg1154Gln missense NM_001377273.1:c.3461G>A NP_001364202.1:p.Arg1154Gln missense NM_001377274.1:c.2594G>A NP_001364203.1:p.Arg865Gln missense NM_005691.4:c.3461G>A NP_005682.2:p.Arg1154Gln missense NC_000012.12:g.21842326C>T NC_000012.11:g.21995260C>T NG_012819.1:g.99369G>A LRG_377:g.99369G>A LRG_377t1:c.3461G>A O60706:p.Arg1154Gln - Protein change
- R1154Q, R865Q
- Other names
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- Canonical SPDI
- NC_000012.12:21842325: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.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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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ABCC9 | - | - |
GRCh38 GRCh37 |
1711 | 1754 |
Conditions - Germline
Condition
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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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Sep 16, 2022 | RCV000024625.8 | |
Pathogenic (3) |
criteria provided, single submitter
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Sep 7, 2023 | RCV000256056.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 20, 2022 | RCV000559460.5 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003335056.1 |
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
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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
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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
(May 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypertrichotic osteochondrodysplasia Cantu type
Affected status: yes
Allele origin:
germline
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Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV001423627.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
Comment:
[ACMG/AMP: PS1, PS2, PS3, PM2, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], is de … (more)
[ACMG/AMP: PS1, PS2, PS3, PM2, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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ABCC9-related disorder
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046082.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a heterozygous change in patients Cantu Syndrome (PMID: PMID: 22610116, 23307537, 22608503, 31828977, 32622958). The c.3461G>A (p.Arg1154Gln) variant … (more)
This variant has been previously reported as a heterozygous change in patients Cantu Syndrome (PMID: PMID: 22610116, 23307537, 22608503, 31828977, 32622958). The c.3461G>A (p.Arg1154Gln) variant is located in a mutational hotspot for pathogenic variations associated with Cantu Syndrome (PMID: 22608503). Different amino acid changes at the same residue (p.R1154W & p.R1154G) have been previously reported in individuals with Cantu Syndrome (PMID: 22608503, 31828977, 29275331). Experimental studies have shown that this non-synonymous change causes abnormal channel function (PMID: 22610116, 33529173). The c.3461G>A (p.Arg1154Gln) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.3461G>A (p.Arg1154Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a discordant effect on protein function. Based on the available evidence, the c.3461G>A (p.Arg1154Gln) variant is classified as Pathogenic. (less)
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Pathogenic
(Sep 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrichotic osteochondrodysplasia Cantu type
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Additional submitter:
CUBI - Core Unit Bioinformatics, Berlin Institute of Health
Accession: SCV002574961.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Clinical Features:
Macrocephaly (present) , Congenital, generalized hypertrichosis (present) , Thick vermilion border (present) , Low anterior hairline (present) , Wide mouth (present)
Sex: female
Tissue: Blood
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Pathogenic
(Sep 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322065.7
First in ClinVar: Oct 10, 2016 Last updated: Sep 14, 2023 |
Comment:
Published functional studies suggest a damaging effect via reduced ATP sensitivity of the potassium channel (Harakalova et al., 2012); Not observed at significant frequency in … (more)
Published functional studies suggest a damaging effect via reduced ATP sensitivity of the potassium channel (Harakalova et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23307537, 31828977, 29275331, 32622958, 32371413, 34056838, 31785789, 33529173, 22610116, 22608503) (less)
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Pathogenic
(Aug 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1O
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000639234.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1154 amino acid residue in ABCC9. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1154 amino acid residue in ABCC9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22608503, 26871653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects ABCC9 function (PMID: 22610116). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 31947). This missense change has been observed in individual(s) with Cantu syndrome (PMID: 22608503, 23307537). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1154 of the ABCC9 protein (p.Arg1154Gln). (less)
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Pathogenic
(Jun 08, 2012)
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no assertion criteria provided
Method: literature only
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HYPERTRICHOTIC OSTEOCHONDRODYSPLASIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000050491.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 5 patients from 3 families with Cantu syndrome (239850), including a mother and 2 daughters originally reported by Grange et al. (2006), van Bon … (more)
In 5 patients from 3 families with Cantu syndrome (239850), including a mother and 2 daughters originally reported by Grange et al. (2006), van Bon et al. (2012) identified heterozygosity for a 3461G-A transition in exon 27 of the ABCC9 gene, resulting in an arg1154-to-gln (R1154Q) substitution at a highly conserved residue in the second type 1 transmembrane domain (TMD2). The mutation was not found in any of the over 5,000 publicly available exomes. In a 15-month-old boy and an unrelated 20-year-old woman with Cantu syndrome, as well as a 21-year-old female patient previously reported by Scurr et al. (2011), Harakalova et al. (2012) identified heterozygosity for the R1554Q mutation in ABCC9. Inside-out patch-clamp experiments in human embryonic kidney cells demonstrated that R1154Q mutant channels have reduced ATP sensitivity compared to wildtype. (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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928833.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800071.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 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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De Novo Mutation in ABCC9 Causes Hypertrichosis Acromegaloid Facial Features Disorder. | Afifi HH | Pediatric dermatology | 2016 | PMID: 26871653 |
Wide clinical variability in conditions with coarse facial features and hypertrichosis caused by mutations in ABCC9. | Czeschik JC | American journal of medical genetics. Part A | 2013 | PMID: 23307537 |
Dominant missense mutations in ABCC9 cause Cantú syndrome. | Harakalova M | Nature genetics | 2012 | PMID: 22610116 |
Cantú syndrome is caused by mutations in ABCC9. | van Bon BW | American journal of human genetics | 2012 | PMID: 22608503 |
Cantú syndrome: report of nine new cases and expansion of the clinical phenotype. | Scurr I | American journal of medical genetics. Part A | 2011 | PMID: 21344641 |
Cantu syndrome in a woman and her two daughters: Further confirmation of autosomal dominant inheritance and review of the cardiac manifestations. | Grange DK | American journal of medical genetics. Part A | 2006 | PMID: 16835932 |
Text-mined citations for rs387907209 ...
HelpRecord last updated May 12, 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.