VCV000039424.41 - ClinVar

NM_004069.6(AP2S1):c.43C>T (p.Arg15Cys)

Germline

Classification

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.

(11)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004069.6(AP2S1):c.43C>T (p.Arg15Cys)

Variation ID: 39424 Accession: VCV000039424.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.32 19: 46846103 (GRCh38) [ NCBI UCSC ] 19: 47349360 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 26, 2024	Oct 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004069.6:c.43C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004060.2:p.Arg15Cys	missense
NM_001301076.3:c.91C>T	NP_001288005.1:p.Arg31Cys	missense
NM_001301078.3:c.43C>T	NP_001288007.1:p.Arg15Cys	missense
NM_001301081.3:c.49C>T	NP_001288010.1:p.Arg17Cys	missense
NM_004069.3:c.43C>T
NM_021575.5:c.43C>T	NP_067586.1:p.Arg15Cys	missense
NC_000019.10:g.46846103G>A
NC_000019.9:g.47349360G>A
NG_033136.1:g.9844C>T
	P53680:p.Arg15Cys

... more HGVS ... less HGVS

Protein change

R15C, R17C, R31C

Other names

Canonical SPDI

NC_000019.10:46846102:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA130281 UniProtKB: P53680#VAR_069570 OMIM: 602242.0001 dbSNP: rs397514498 VarSome

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
Gene	OMIM	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.
AP2S1		-	-	GRCh38 GRCh37	117	133

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.
Familial hypocalciuric hypercalcemia 3	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Oct 23, 2024	RCV000032619.15
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 8, 2024	RCV001228882.32
AP2S1-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 16, 2024	RCV004748539.1

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.
Pathogenic (Jun 02, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002525371.2 First in ClinVar: Jun 10, 2022 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate this variant impairs the role of AP2S1 in extracellular calcium homeostasis by affected CaSR endocytosis and decreasing sensitivity of cells to … (more) Published functional studies demonstrate this variant impairs the role of AP2S1 in extracellular calcium homeostasis by affected CaSR endocytosis and decreasing sensitivity of cells to extracellular calcium (Nesbit et al., 2013; Hannan et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26082470, 27913609, 27050234, 31672324, 23222959, 33729479, 33168530, 24731014, 31723423) (less)
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypocalciuric hypercalcemia 3 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893538.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypocalciuric hypercalcemia 3 Affected status: yes Allele origin: germline	3billion Accession: SCV002318700.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (1) PubMed: 23222959 Comment: Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039424, PMID:23222959). … (more) Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039424, PMID:23222959). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039425,VCV000039426, PMID:23222959,23222959). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.763>=0.6, 3CNET: 0.828>=0.75). A missense variant is a common mechanism associated with Hypocalciuric hypercalcemia, type III. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Delayed speech and language development (present) , Hypercalcemia (present)
Pathogenic (May 09, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypocalciuric hypercalcemia, familial, type III Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000593215.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015
Pathogenic (Nov 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypocalciuric hypercalcemia 3 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175283.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (2) PubMed: 26082470‚ 31723423 Comment: The AP2S1 c.43C>T variant is classified as Pathogenic (PS4, PM2, PM5, PP1, PP3) The AP2S1 c.43C>T variant is a single nucleotide change in exon 2/5 … (more) The AP2S1 c.43C>T variant is classified as Pathogenic (PS4, PM2, PM5, PP1, PP3) The AP2S1 c.43C>T variant is a single nucleotide change in exon 2/5 of the AP2S1 gene, which is predicted to change the amino acid arginine at position 15 in the protein to cysteine. The variant has been reported in several probands with a clinical presentation of familial hypocalciuric hypercalcemia (HGMD: CM1212084) (PS4). This variant is absent from population databases (PM2). This variant has been shown to segregate with disease in a 2019 study (Wong et al, 2019; PMID:31723423) (PP1). HEK-CaSR cells expressing Arg15 missense AP2-sigma-2 variants were found to have half-maximal effective concentration (EC50) values that were significantly higher than cells expressing the wild-type AP2-sigma-2 protein (Hannan et al; 2015; PMID:26082470) (PS3_moderate). This variant is a missense change at an amino acid residue where the different missense changes p.Arg15His and p.Arg15Leu has been seen before (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs397514498) and in the HGMD database: CM1212084. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 39424). (less)
Pathogenic (Jan 08, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001401307.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 23222959‚ 24731014‚ 26082470‚ 27050234 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 15 of the AP2S1 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 15 of the AP2S1 protein (p.Arg15Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia type 3 (PMID: 23222959, 24731014, 26082470, 27050234). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39424). 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). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001501747.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Oct 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypocalciuric hypercalcemia 3 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005380240.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: ACMG criteria used: PS3, PS4, PM2, PM5, PP3
Pathogenic (Jan 01, 2013)	no assertion criteria provided Method: literature only	HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE III Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056382.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (3) PubMed: 1524075‚ 20133464‚ 23222959 Comment on evidence: In affected members of 2 unrelated 3-generation families segregating autosomal dominant hypocalciuric hypercalcemia mapping to chromosome 19q13 (HHC3; 600740), 1 of which was a kindred … (more) In affected members of 2 unrelated 3-generation families segregating autosomal dominant hypocalciuric hypercalcemia mapping to chromosome 19q13 (HHC3; 600740), 1 of which was a kindred from Oklahoma originally described by McMurtry et al. (1992) and the other a kindred from Northern Ireland originally reported by Nesbit et al. (2010), Nesbit et al. (2013) identified heterozygosity for a C-T transition in exon 2 of the AP2S1 gene, resulting in an arg15-to-cys (R15C) substitution at an evolutionarily conserved residue. The R15C mutation was subsequently identified in heterozygosity in 4 additional unrelated probands with hypocalciuric hypercalcemia. 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)
Pathogenic (Mar 08, 2024)	no assertion criteria provided Method: clinical testing	Familial hypocalciuric hypercalcemia 3 Affected status: yes Allele origin: maternal	Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute Accession: SCV004708208.1 First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024
Pathogenic (Aug 16, 2024)	no assertion criteria provided Method: clinical testing	AP2S1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005361813.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The AP2S1 c.43C>T variant is predicted to result in the amino acid substitution p.Arg15Cys. This variant has been reported to be pathogenic for familial hypocalciuric … (more) The AP2S1 c.43C>T variant is predicted to result in the amino acid substitution p.Arg15Cys. This variant has been reported to be pathogenic for familial hypocalciuric hypercalcemia (FHH) (Nesbit et al. 2013. PubMed ID: 23222959). 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 are 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). This variant has not been reported in a large population database, and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/39424/). This variant is interpreted as pathogenic. (less)
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Comment:

Published functional studies demonstrate this variant impairs the role of AP2S1 in extracellular calcium homeostasis by affected CaSR endocytosis and decreasing sensitivity of cells to extracellular calcium (Nesbit et al., 2013; Hannan et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26082470, 27913609, 27050234, 31672324, 23222959, 33729479, 33168530, 24731014, 31723423)

Comment:

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039424, PMID:23222959). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039425,VCV000039426, PMID:23222959,23222959). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.763>=0.6, 3CNET: 0.828>=0.75). A missense variant is a common mechanism associated with Hypocalciuric hypercalcemia, type III. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The AP2S1 c.43C>T variant is classified as Pathogenic (PS4, PM2, PM5, PP1, PP3) The AP2S1 c.43C>T variant is a single nucleotide change in exon 2/5 of the AP2S1 gene, which is predicted to change the amino acid arginine at position 15 in the protein to cysteine. The variant has been reported in several probands with a clinical presentation of familial hypocalciuric hypercalcemia (HGMD: CM1212084) (PS4). This variant is absent from population databases (PM2). This variant has been shown to segregate with disease in a 2019 study (Wong et al, 2019; PMID:31723423) (PP1). HEK-CaSR cells expressing Arg15 missense AP2-sigma-2 variants were found to have half-maximal effective concentration (EC50) values that were significantly higher than cells expressing the wild-type AP2-sigma-2 protein (Hannan et al; 2015; PMID:26082470) (PS3_moderate). This variant is a missense change at an amino acid residue where the different missense changes p.Arg15His and p.Arg15Leu has been seen before (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs397514498) and in the HGMD database: CM1212084. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 39424).

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 15 of the AP2S1 protein (p.Arg15Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia type 3 (PMID: 23222959, 24731014, 26082470, 27050234). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39424). 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). For these reasons, this variant has been classified as Pathogenic.

Comment:

The AP2S1 c.43C>T variant is predicted to result in the amino acid substitution p.Arg15Cys. This variant has been reported to be pathogenic for familial hypocalciuric hypercalcemia (FHH) (Nesbit et al. 2013. PubMed ID: 23222959). 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 are 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). This variant has not been reported in a large population database, and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/39424/). This variant is interpreted as pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A Hong Kong Chinese kindred with familial hypocalciuric hypercalcaemia caused by AP2S1 mutation.	Wong FCK	F1000Research	2019	PMID: 31723423
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
Identification of a second kindred with familial hypocalciuric hypercalcemia type 3 (FHH3) narrows localization to a <3.5 megabase pair region on chromosome 19q13.3.	Nesbit MA	The Journal of clinical endocrinology and metabolism	2010	PMID: 20133464
Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia.	McMurtry CT	The American journal of medicine	1992	PMID: 1524075

Text-mined citations for rs397514498 ...

These 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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_004069.6(AP2S1):c.43C>T (p.Arg15Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397514498 ...