ClinVar Genomic variation as it relates to human health
NM_004069.6(AP2S1):c.44G>T (p.Arg15Leu)
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>T (p.Arg15Leu)
Variation ID: 39425 Accession: VCV000039425.24
- 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 Mar 16, 2024 Feb 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004069.6:c.44G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004060.2:p.Arg15Leu missense NM_001301076.3:c.92G>T NP_001288005.1:p.Arg31Leu missense NM_001301078.3:c.44G>T NP_001288007.1:p.Arg15Leu missense NM_001301081.3:c.50G>T NP_001288010.1:p.Arg17Leu missense NM_004069.3:c.44G>T NM_021575.5:c.44G>T NP_067586.1:p.Arg15Leu missense NC_000019.10:g.46846102C>A NC_000019.9:g.47349359C>A NG_033136.1:g.9845G>T P53680:p.Arg15Leu - Protein change
- R15L, R31L, R17L
- Other names
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- Canonical SPDI
- NC_000019.10:46846101:C:A
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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
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 (4) |
criteria provided, single submitter
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Jan 1, 2019 | RCV000032620.8 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 12, 2024 | RCV001220777.18 | |
AP2S1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Feb 16, 2024 | RCV003904882.1 |
Submissions - Germline
Classification
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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 12, 2017)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002072105.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Pathogenic
(Aug 15, 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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552072.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial hypocalciuric hypercalcemia 3
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001441026.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Pathogenic
(Jan 12, 2024)
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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: SCV001392788.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 15 of the AP2S1 protein (p.Arg15Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 15 of the AP2S1 protein (p.Arg15Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypocalciuric hypercalcemia type 3 (PMID: 23222959, 24081735, 24731014, 26082470, 27913609). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39425). 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). 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
(Oct 09, 2022)
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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: SCV002578288.2
First in ClinVar: Oct 15, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate this variant disrupts extracellular-calcium homeostasis with a dominant-negative effect of the mutant protein on calcium response (Nesbit et al., 2013; Hannan … (more)
Published functional studies demonstrate this variant disrupts extracellular-calcium homeostasis with a dominant-negative effect of the mutant protein on calcium response (Nesbit et al., 2013; Hannan et al., 2015); Not observed in large population cohorts (gnomAD); 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: 27050234, 25993639, 24731014, 23222959, 27913609, 26082470, 28176280, 24081735, 31391146, 31672324, 32430905) (less)
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Pathogenic
(Feb 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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AP2S1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004718890.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The AP2S1 c.44G>T variant is predicted to result in the amino acid substitution p.Arg15Leu. This variant has been reported to be pathogenic for familial hypocalciuric … (more)
The AP2S1 c.44G>T variant is predicted to result in the amino acid substitution p.Arg15Leu. This variant has been reported to be pathogenic for familial hypocalciuric hypercalcemia (FHH) (Nesbit et al. 2013. PubMed ID: 23222959; Hendy et al. 2014. PubMed ID: 24731014; Hannan et al. 2015. PubMed ID: 26082470; Mariathasan et al. 2020. PubMed ID: 32430905). Nesbit et al. found three different amino acid changes at the p.Arg15 codon (p.Arg15Cys, p.Arg15His and p.Arg15Leu) in FHH patients who were negative for CASR defects. These alterations at the p.Arg15 codon resulted in decreased sensitivity of CaSR-expressing cells to extracellular calcium, reduced CaSR endocytosis, and decreased intracellular signaling. Of note, cinacalcet-mediated allosteric modulation of the calcium-sensing receptor has been recently demonstrated to be able to correct the loss of function of AP2S1 alterations at the p.Arg15 codon (Howles et al. 2016.PubMed ID: 27276582). In summary, this variant is interpreted 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: SCV000056383.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 16, 2021 |
Comment on evidence:
In 4 unrelated probands with hypocalciuric hypercalcemia (HHC3; 600740), Nesbit et al. (2013) identified heterozygosity for a G-T transversion in exon 2 of the AP2S1 … (more)
In 4 unrelated probands with hypocalciuric hypercalcemia (HHC3; 600740), Nesbit et al. (2013) identified heterozygosity for a G-T transversion in exon 2 of the AP2S1 gene, resulting in an arg15-to-leu (R15L) 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. In a Japanese infant with HHC3, Fujisawa et al. (2013) identified heterozygosity for the R15L mutation in the AP2S1 gene. The mutation was found by sequencing of the APS2S1 gene and was not present in either parent or in her asymptomatic sib. Functional studies were not performed. The authors noted that this patient had hypercalcemia and normal parathyroid hormone with hypercalciuria, indicating that HHC3 may present without hypocalciuria. (less)
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Pathogenic
(May 06, 2020)
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no assertion criteria provided
Method: clinical testing
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Familial hypocalciuric hypercalcemia 3
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001469179.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Pathogenic
(Mar 08, 2024)
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no assertion criteria provided
Method: clinical testing
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Familial hypocalciuric hypercalcemia 3
Affected status: yes
Allele origin:
de novo
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Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute
Accession: SCV004708179.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
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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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AP2S1 and GNA11 mutations - not a common cause of familial hypocalciuric hypercalcemia. | Hovden S | European journal of endocrinology | 2017 | PMID: 27913609 |
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 |
Identification of AP2S1 mutation and effects of low calcium formula in an infant with hypercalcemia and hypercalciuria. | Fujisawa Y | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 24081735 |
Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. | Nesbit MA | Nature genetics | 2013 | PMID: 23222959 |
Text-mined citations for rs397514499 ...
HelpRecord last updated May 19, 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.