VCV000372315.21 - ClinVar

NM_000388.4(CASR):c.73C>T (p.Arg25Ter)

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.

(10)

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/Likely 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_000388.4(CASR):c.73C>T (p.Arg25Ter)

Variation ID: 372315 Accession: VCV000372315.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q21.1 3: 122254262 (GRCh38) [ NCBI UCSC ] 3: 121973109 (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	Jan 9, 2017	Nov 24, 2024	May 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000388.4:c.73C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000379.3:p.Arg25Ter	nonsense
NM_001178065.2:c.73C>T	NP_001171536.2:p.Arg25Ter	nonsense
NC_000003.12:g.122254262C>T
NC_000003.11:g.121973109C>T
NG_009058.1:g.75580C>T

... more HGVS ... less HGVS

Protein change

R25*

Other names

Canonical SPDI

NC_000003.12:122254261:C:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00010

Links

ClinGen: CA2569414 dbSNP: rs201633414 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.
CASR		No evidence available	No evidence available	GRCh38 GRCh37	2735	2758

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.
not provided	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 1, 2024	RCV000413560.11
Autosomal dominant hypocalcemia 1 Familial hypocalciuric hypercalcemia	Pathogenic (1)	criteria provided, single submitter	Dec 28, 2023	RCV000457695.9
CASR-related calcium metabolism disorders	Pathogenic (1)	criteria provided, single submitter	Aug 30, 2023	RCV003333060.1
Nephrolithiasis/nephrocalcinosis	Pathogenic (1)	criteria provided, single submitter	Aug 11, 2021	RCV004022152.1
Autosomal dominant hypocalcemia 1	Pathogenic (1)	criteria provided, single submitter	May 21, 2020	RCV004786676.1
Neonatal severe primary hyperparathyroidism	Pathogenic (1)	criteria provided, single submitter	Apr 18, 2024	RCV004586698.1

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.
Likely pathogenic (Dec 14, 2016)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000612679.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Publications: PubMed (2) PubMed: 16649980‚ 21521328
Pathogenic (May 04, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000490452.2 First in ClinVar: Jan 09, 2017 Last updated: May 03, 2018	Comment: The R25X nonsense variant in the CASR gene has been reported previously in patients with primary hyperparathyroidism and familial hypocacliuric hypercalcemia (Frank-Raue et al, 2011; … (more) The R25X nonsense variant in the CASR gene has been reported previously in patients with primary hyperparathyroidism and familial hypocacliuric hypercalcemia (Frank-Raue et al, 2011; Ward et al., 2006). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the R25X variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. In summary, we interpret R25X as a pathogenic variant. (less)
Pathogenic (Dec 28, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypocalciuric hypercalcemia Autosomal dominant hypocalcemia 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000550973.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 11807402‚ 14985373‚ 22422767‚ 16649980‚ 21521328 Comment: This sequence change creates a premature translational stop signal (p.Arg25) in the CASR gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg25) in the CASR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CASR are known to be pathogenic (PMID: 11807402, 14985373, 22422767). This variant is present in population databases (rs201633414, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with familial hypocalciuric hypercalcaemia (FHH) and primary hyperparathyroidism (HPT) (PMID: 16649980, 21521328). ClinVar contains an entry for this variant (Variation ID: 372315). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CASR-related calcium metabolism disorders Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041078.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (Aug 11, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Nephrolithiasis/nephrocalcinosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002673965.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 16649980‚ 21521328‚ 30407919 Comment: The p.R25* pathogenic mutation (also known as c.73C>T), located in coding exon 1 of the CASR gene, results from a C to T substitution at … (more) The p.R25* pathogenic mutation (also known as c.73C>T), located in coding exon 1 of the CASR gene, results from a C to T substitution at nucleotide position 73. This changes the amino acid from an arginine to a stop codon within coding exon 1. This alteration has been identified in multiple families with familial hypocalciuric hypercalcemia (FHH) (Ward BK et al. Clin Endocrinol (Oxf), 2006 May;64:580-7; García-Castaño A et al. Eur J Endocrinol, 2019 Jan;180:59-70). Additionally, this alteration was identified in an individual diagnosed with hypercalcemia, hyperparathyroidism, kidney stones and hypertension (Frank-Raue K et al. Clin Endocrinol (Oxf), 2011 Jul;75:50-5). 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)
Pathogenic (Apr 18, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Neonatal severe primary hyperparathyroidism Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005077214.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (1) PubMed: 22422767 Comment: Variant summary: CASR c.73C>T (p.Arg25X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is … (more) Variant summary: CASR c.73C>T (p.Arg25X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251326 control chromosomes. c.73C>T has been reported in the literature at a homozygous state in at-least one individual affected with Neonatal Severe Hyperparathyroidism and at a heterozygous state in one patient with familial hypocalciuric hypercalcaemia (example, Hannan_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22422767). ClinVar contains an entry for this variant (Variation ID: 372315). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Likely pathogenic (May 01, 2024)	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: SCV005051184.5 First in ClinVar: Jun 17, 2024 Last updated: Oct 20, 2024	Comment: CASR: PVS1:Strong, PS4:Moderate, PM2:Supporting Number of individuals with the variant: 1
Pathogenic (May 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant hypocalcemia 1 Affected status: no Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399314.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 16649980‚ 21521328 Comment: A heterozygous nonsense variant was identified, NM_000388.3(CASR):c.73C>T in exon 2 of 7 of the CASR gene. This nonsense variant is predicted to create a change … (more) A heterozygous nonsense variant was identified, NM_000388.3(CASR):c.73C>T in exon 2 of 7 of the CASR gene. This nonsense variant is predicted to create a change of arginine to a stop at amino acid position 25 of the protein, NP_000379.2(CASR):p.(Arg25*) resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a frequency of 0.0018% (5 heterozygotes). It has been previously reported as pathogenic and in patients with mild hypercalcaemia and hyperparathyroidism (ClinVar, Ward, B. et al. (2006), Frank-Raue, K. et al. (2011)). It has also been shown to segregate with the disease in one family (Ward, B. et al. (2006)). Other variants predicted to cause NMD have been reported as pathogenic in individuals with hyperparathyroidism and hypercalcemia (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930863.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957148.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021

Comment:

The R25X nonsense variant in the CASR gene has been reported previously in patients with primary hyperparathyroidism and familial hypocacliuric hypercalcemia (Frank-Raue et al, 2011; Ward et al., 2006). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the R25X variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. In summary, we interpret R25X as a pathogenic variant.

Comment:

This sequence change creates a premature translational stop signal (p.Arg25*) in the CASR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CASR are known to be pathogenic (PMID: 11807402, 14985373, 22422767). This variant is present in population databases (rs201633414, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with familial hypocalciuric hypercalcaemia (FHH) and primary hyperparathyroidism (HPT) (PMID: 16649980, 21521328). ClinVar contains an entry for this variant (Variation ID: 372315). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.R25* pathogenic mutation (also known as c.73C>T), located in coding exon 1 of the CASR gene, results from a C to T substitution at nucleotide position 73. This changes the amino acid from an arginine to a stop codon within coding exon 1. This alteration has been identified in multiple families with familial hypocalciuric hypercalcemia (FHH) (Ward BK et al. Clin Endocrinol (Oxf), 2006 May;64:580-7; García-Castaño A et al. Eur J Endocrinol, 2019 Jan;180:59-70). Additionally, this alteration was identified in an individual diagnosed with hypercalcemia, hyperparathyroidism, kidney stones and hypertension (Frank-Raue K et al. Clin Endocrinol (Oxf), 2011 Jul;75:50-5). 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.

Comment:

Variant summary: CASR c.73C>T (p.Arg25X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251326 control chromosomes. c.73C>T has been reported in the literature at a homozygous state in at-least one individual affected with Neonatal Severe Hyperparathyroidism and at a heterozygous state in one patient with familial hypocalciuric hypercalcaemia (example, Hannan_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22422767). ClinVar contains an entry for this variant (Variation ID: 372315). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

A heterozygous nonsense variant was identified, NM_000388.3(CASR):c.73C>T in exon 2 of 7 of the CASR gene. This nonsense variant is predicted to create a change of arginine to a stop at amino acid position 25 of the protein, NP_000379.2(CASR):p.(Arg25*) resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a frequency of 0.0018% (5 heterozygotes). It has been previously reported as pathogenic and in patients with mild hypercalcaemia and hyperparathyroidism (ClinVar, Ward, B. et al. (2006), Frank-Raue, K. et al. (2011)). It has also been shown to segregate with the disease in one family (Ward, B. et al. (2006)). Other variants predicted to cause NMD have been reported as pathogenic in individuals with hyperparathyroidism and hypercalcemia (ClinVar). Based on information available at the time of curation, this variant has been classified 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
Novel mutations associated with inherited human calcium-sensing receptor disorders: A clinical genetic study.	García-Castaño A	European journal of endocrinology	2019	PMID: 30407919
Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites.	Hannan FM	Human molecular genetics	2012	PMID: 22422767
Inactivating calcium-sensing receptor mutations in patients with primary hyperparathyroidism.	Frank-Raue K	Clinical endocrinology	2011	PMID: 21521328
Novel mutations in the calcium-sensing receptor gene associated with biochemical and functional differences in familial hypocalciuric hypercalcaemia.	Ward BK	Clinical endocrinology	2006	PMID: 16649980
Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications.	Warner J	Journal of medical genetics	2004	PMID: 14985373
Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds.	Simonds WF	Medicine	2002	PMID: 11807402

Text-mined citations for rs201633414 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000388.4(CASR):c.73C>T (p.Arg25Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201633414 ...