ClinVar Genomic variation as it relates to human health
NM_004069.6(AP2S1):c.44G>A (p.Arg15His)
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_004069.6(AP2S1):c.44G>A (p.Arg15His)
Variation ID: 39426 Accession: VCV000039426.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.32 19: 46846102 (GRCh38) [ NCBI UCSC ] 19: 47349359 (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 14, 2024 Nov 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004069.6:c.44G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004060.2:p.Arg15His missense NM_001301076.3:c.92G>A NP_001288005.1:p.Arg31His missense NM_001301078.3:c.44G>A NP_001288007.1:p.Arg15His missense NM_001301081.3:c.50G>A NP_001288010.1:p.Arg17His missense NM_021575.5:c.44G>A NP_067586.1:p.Arg15His missense NC_000019.10:g.46846102C>T NC_000019.9:g.47349359C>T NG_033136.1:g.9845G>A P53680:p.Arg15His - Protein change
- R15H, R31H, R17H
- Other names
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- Canonical SPDI
- NC_000019.10:46846101: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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AP2S1 | - | - |
GRCh38 GRCh37 |
113 | 129 |
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
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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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Jul 15, 2022 | RCV000032621.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 18, 2023 | RCV000520417.10 |
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
(Jul 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial hypocalciuric hypercalcemia 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761869.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Mar 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial hypocalciuric hypercalcemia 3
Affected status: unknown
Allele origin:
germline
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Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002549732.1
First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022 |
Comment:
AP2S1 p.Arg15His is one of several pathogenic variants affecting Arg15 and causing familial hypocalciuric hypercalcaemia (FHH) type 3. Functional studies demonstrate decreased sensitivity of p.Arg15His … (more)
AP2S1 p.Arg15His is one of several pathogenic variants affecting Arg15 and causing familial hypocalciuric hypercalcaemia (FHH) type 3. Functional studies demonstrate decreased sensitivity of p.Arg15His to extracellular calcium and impaired calcium-sensing receptor internalisation (PMID: 23222959, 29420171). (less)
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Pathogenic
(Aug 31, 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: SCV000617857.3
First in ClinVar: Dec 19, 2017 Last updated: Sep 14, 2023 |
Comment:
Published functional studies demonstrate a decreased sensitivity to extracellular calcium and reduced CaSR endocytosis (Nesbit et al., 2013; Gorvin CM et al., 2018); In silico … (more)
Published functional studies demonstrate a decreased sensitivity to extracellular calcium and reduced CaSR endocytosis (Nesbit et al., 2013; Gorvin CM et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; This variant is associated with the following publications: (PMID: 32047691, 26082470, 27913609, 24731014, 27761240, 27050234, 25993639, 23222959, 29325022, 29420171) (less)
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Pathogenic
(Nov 18, 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: SCV001412232.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 15 of the AP2S1 protein (p.Arg15His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 15 of the AP2S1 protein (p.Arg15His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with AP2S1-related conditions (PMID: 23222959, 24731014, 26082470, 27050234, 27761240, 29325022). ClinVar contains an entry for this variant (Variation ID: 39426). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects AP2S1 function (PMID: 23222959, 26082470, 29325022, 29420171). This variant disrupts the p.Arg15 amino acid residue in AP2S1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23222959, 24731014, 26082470, 27050234). 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
(Jan 01, 2013)
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no assertion criteria provided
Method: literature only
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HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE III
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056384.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 3 unrelated probands with hypocalciuric hypercalcemia (HHC3; 600740), Nesbit et al. (2013) identified heterozygosity for a G-A transition in exon 2 of the AP2S1 … (more)
In 3 unrelated probands with hypocalciuric hypercalcemia (HHC3; 600740), Nesbit et al. (2013) identified heterozygosity for a G-A transition in exon 2 of the AP2S1 gene, resulting in an arg15-to-his (R15H) substitution at an evolutionarily conserved residue. Functional analysis in transiently transfected HEK293 cells showed a rightward shift in Ca(2+) concentration-response curves with the AP2S1 mutant compared to wildtype, indicating a decrease in the sensitivity of cells expressing CASR (601199) to extracellular calcium. (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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AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity. | Gorvin CM | Cell reports | 2018 | PMID: 29420171 |
Large-scale exome datasets reveal a new class of adaptor-related protein complex 2 sigma subunit (AP2σ) mutations, located at the interface with the AP2 alpha subunit, that impair calcium-sensing receptor signalling. | Gorvin CM | Human molecular genetics | 2018 | PMID: 29325022 |
Multiple endocrine neoplasia phenocopy revealed as a co-occurring neuroendocrine tumor and familial hypocalciuric hypercalcemia type 3. | Hovden S | Clinical case reports | 2016 | PMID: 27761240 |
Cinacalcet for Symptomatic Hypercalcemia Caused by AP2S1 Mutations. | Howles SA | The New England journal of medicine | 2016 | PMID: 27050234 |
Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects. | Hannan FM | Human molecular genetics | 2015 | PMID: 26082470 |
Codon Arg15 mutations of the AP2S1 gene: common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations. | Hendy GN | The Journal of clinical endocrinology and metabolism | 2014 | PMID: 24731014 |
Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. | Nesbit MA | Nature genetics | 2013 | PMID: 23222959 |
Text-mined citations for rs397514499 ...
HelpRecord last updated Jun 23, 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.