Variant summary: CASR c.2038C>T (p.Arg680Cys) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251154 control chromosomes. c.2038C>T has been widely reported in the literature in individuals affected with features of Familial Hypocalciuric Hypercalcemia/Familial benign hypercalcemia (example, Pearce_1995, Mouly_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Pearce_1996). The most pronounced variant effect results in lack of responsiveness to gadolinium or calcium ions (<10% of normal activity) and severely reduced N-linked glycosylation despite normal receptor expression on the cell membrane. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000388.4(CASR):c.2038C>T (p.Arg680Cys)
Germline
Classification
Help
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.
(3)
Help
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
3
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.2038C>T (p.Arg680Cys)
Variation ID: 410347 Accession: VCV000410347.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q21.1 3: 122283992 (GRCh38) [ NCBI UCSC ] 3: 122002839 (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 Oct 10, 2018 Feb 28, 2024 Nov 13, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000388.4:c.2038C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000379.3:p.Arg680Cys missense NM_001178065.2:c.2068C>T NP_001171536.2:p.Arg690Cys missense NC_000003.12:g.122283992C>T NC_000003.11:g.122002839C>T NG_009058.1:g.105310C>T - Protein change
- R680C, R690C
- Other names
- -
- Canonical SPDI
- NC_000003.12:122283991: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
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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 |
2727 | 2750 | |
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 (1) |
criteria provided, single submitter
|
Jan 27, 2022 | RCV001289355.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 13, 2023 | RCV002230400.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 20, 2022 | RCV002307504.8 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Oct 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypocalciuric hypercalcemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002600597.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: CASR c.2038C>T (p.Arg680Cys) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein … (more)
Variant summary: CASR c.2038C>T (p.Arg680Cys) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251154 control chromosomes. c.2038C>T has been widely reported in the literature in individuals affected with features of Familial Hypocalciuric Hypercalcemia/Familial benign hypercalcemia (example, Pearce_1995, Mouly_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Pearce_1996). The most pronounced variant effect results in lack of responsiveness to gadolinium or calcium ions (<10% of normal activity) and severely reduced N-linked glycosylation despite normal receptor expression on the cell membrane. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV001477106.2
First in ClinVar: Jan 26, 2021 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant caused significant alterations in calcium potency and/or efficacy (PMID: 8878438, 22798347, 17284438). Computational tools predict that this variant is damaging. (less)
|
|
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Pathogenic
(Nov 13, 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: SCV000550985.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 680 of the CASR protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 680 of the CASR protein (p.Arg680Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia and/or neonatal severe hyperparathyroidism (PMID: 8675635, 15241688, 32347971, 32386559). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410347). 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 disruptive. Experimental studies have shown that this missense change affects CASR function (PMID: 8878438, 17284438, 19389809, 22798347, 23372019, 32386559). This variant disrupts the p.Arg680 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19179454, 22798347, 23372019, 26646938, 26963950, 27666534, 32347971; Invitae). 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)
|
Comment:
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant caused significant alterations in calcium potency and/or efficacy (PMID: 8878438, 22798347, 17284438). Computational tools predict that this variant is damaging.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 680 of the CASR protein (p.Arg680Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia and/or neonatal severe hyperparathyroidism (PMID: 8675635, 15241688, 32347971, 32386559). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410347). 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 disruptive. Experimental studies have shown that this missense change affects CASR function (PMID: 8878438, 17284438, 19389809, 22798347, 23372019, 32386559). This variant disrupts the p.Arg680 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19179454, 22798347, 23372019, 26646938, 26963950, 27666534, 32347971; Invitae). 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.
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:
Variant summary: CASR c.2038C>T (p.Arg680Cys) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251154 control chromosomes. c.2038C>T has been widely reported in the literature in individuals affected with features of Familial Hypocalciuric Hypercalcemia/Familial benign hypercalcemia (example, Pearce_1995, Mouly_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Pearce_1996). The most pronounced variant effect results in lack of responsiveness to gadolinium or calcium ions (<10% of normal activity) and severely reduced N-linked glycosylation despite normal receptor expression on the cell membrane. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant caused significant alterations in calcium potency and/or efficacy (PMID: 8878438, 22798347, 17284438). Computational tools predict that this variant is damaging.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 680 of the CASR protein (p.Arg680Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia and/or neonatal severe hyperparathyroidism (PMID: 8675635, 15241688, 32347971, 32386559). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410347). 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 disruptive. Experimental studies have shown that this missense change affects CASR function (PMID: 8878438, 17284438, 19389809, 22798347, 23372019, 32386559). This variant disrupts the p.Arg680 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19179454, 22798347, 23372019, 26646938, 26963950, 27666534, 32347971; Invitae). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Challenges in diagnosis and management of neonatal hyperparathyroidism in a resource-limited country: a case series from a Sudanese family. | Hassan SS | The Pan African medical journal | 2021 | PMID: 34887979 |
| Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population. | Dershem R | American journal of human genetics | 2020 | PMID: 32386559 |
| Clinical characteristics of familial hypocalciuric hypercalcaemia type 1: A multicentre study of 77 adult patients. | Mouly C | Clinical endocrinology | 2020 | PMID: 32347971 |
| Expanding the spectrum of genetic variants in the calcium-sensing receptor (CASR) gene in hypercalcemic individuals. | Nissen PH | Clinical endocrinology | 2019 | PMID: 31433865 |
| Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype. | Glaudo M | European journal of endocrinology | 2016 | PMID: 27666534 |
| Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences. | Vargas-Poussou R | The Journal of clinical endocrinology and metabolism | 2016 | PMID: 26963950 |
| GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts. | Mayr B | European journal of endocrinology | 2016 | PMID: 26646938 |
| Impact of clinically relevant mutations on the pharmacoregulation and signaling bias of the calcium-sensing receptor by positive and negative allosteric modulators. | Leach K | Endocrinology | 2013 | PMID: 23372019 |
| Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor. | Leach K | Endocrinology | 2012 | PMID: 22798347 |
| Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1). | Turner JJ | Human mutation | 2010 | PMID: 19953642 |
| Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants. | White E | Molecular endocrinology (Baltimore, Md.) | 2009 | PMID: 19389809 |
| Calcium-sensing receptor mutations and denaturing high performance liquid chromatography. | Cole DE | Journal of molecular endocrinology | 2009 | PMID: 19179454 |
| Structure and function of the human calcium-sensing receptor: insights from natural and engineered mutations and allosteric modulators. | Hu J | Journal of cellular and molecular medicine | 2007 | PMID: 17979873 |
| Rescue of calcium-sensing receptor mutants by allosteric modulators reveals a conformational checkpoint in receptor biogenesis. | Huang Y | The Journal of biological chemistry | 2007 | PMID: 17284438 |
| Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy. | Waller S | European journal of pediatrics | 2004 | PMID: 15241688 |
| A novel mutation in Ca2+-sensing receptor gene in familial hypocalciuric hypercalcemia. | Nakayama T | Endocrine | 2001 | PMID: 11762699 |
| Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. | Hendy GN | Human mutation | 2000 | PMID: 11013439 |
| Functional characterization of calcium-sensing receptor mutations expressed in human embryonic kidney cells. | Pearce SH | The Journal of clinical investigation | 1996 | PMID: 8878438 |
| Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. | Pearce SH | The Journal of clinical investigation | 1995 | PMID: 8675635 |
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Text-mined citations for rs767363250 ...
HelpThese 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 10, 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.