ClinVar Genomic variation as it relates to human health
NM_000388.4(CASR):c.73C>T (p.Arg25Ter)
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
-
NM_000388.4(CASR):c.73C>T (p.Arg25Ter)
Variation ID: 372315 Accession: VCV000372315.18
- 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 Aug 4, 2024 May 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_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 - Protein change
- R25*
- Other names
- -
- Canonical SPDI
- NC_000003.12:122254261:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
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
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 | ||
---|---|---|---|---|---|---|
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 |
2724 | 2747 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2024 | RCV000413560.9 | |
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 |
Pathogenic (1) |
criteria provided, single submitter
|
Apr 18, 2024 | RCV004586698.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 11, 2021 | RCV004022152.1 |
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
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 |
|
|
Pathogenic
(May 04, 2016)
|
criteria provided, single submitter
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
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 |
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
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
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 |
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
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 |
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
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005051184.3
First in ClinVar: Jun 17, 2024 Last updated: Aug 04, 2024 |
Comment:
CASR: PVS1:Strong, PS4:Moderate, PM2:Supporting
Number of individuals with the variant: 1
|
|
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 |
|
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 |
---|---|---|---|---|
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 ...
HelpRecord last updated Sep 29, 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.