ClinVar Genomic variation as it relates to human health
NM_000388.4(CASR):c.2039G>A (p.Arg680His)
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_000388.4(CASR):c.2039G>A (p.Arg680His)
Variation ID: 237763 Accession: VCV000237763.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q21.1 3: 122283993 (GRCh38) [ NCBI UCSC ] 3: 122002840 (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 Jul 1, 2016 Feb 28, 2024 Sep 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000388.4:c.2039G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000379.3:p.Arg680His missense NM_001178065.2:c.2069G>A NP_001171536.2:p.Arg690His missense NC_000003.12:g.122283993G>A NC_000003.11:g.122002840G>A NG_009058.1:g.105311G>A - Protein change
- R680H, R690H
- Other names
- p.Arg680His
- Canonical SPDI
- NC_000003.12:122283992:G: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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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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CASR | No evidence available | No evidence available |
GRCh38 GRCh37 |
2575 | 2598 |
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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 25, 2023 | RCV000231951.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 9, 2023 | RCV000991741.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2022 | RCV002494624.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 12, 2023 | RCV003235152.1 |
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
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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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Likely pathogenic
(Sep 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV000284788.7
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects CASR function (PMID: 22798347, 23372019). 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. ClinVar contains an entry for this variant (Variation ID: 237763). This missense change has been observed in individuals with CASR-related conditions (PMID: 19179454, 26646938, 26963950, 27666534, 32347971; Invitae). This variant is present in population databases (rs773146939, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 680 of the CASR protein (p.Arg680His). (less)
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Likely pathogenic
(Apr 11, 2019)
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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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Athena Diagnostics Inc
Accession: SCV001143434.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have … (more)
The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Damaging to protein function(s) relevant to disease mechanism. (less)
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Pathogenic
(Mar 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial hypocalciuric hypercalcemia 1
Neonatal severe primary hyperparathyroidism Autosomal dominant hypocalcemia 1 Epilepsy, idiopathic generalized, susceptibility to, 8
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002794697.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypocalciuric hypercalcemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934483.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: CASR c.2039G>A (p.Arg680His) 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.2039G>A (p.Arg680His) 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 8e-06 in 251122 control chromosomes. c.2039G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (FHH) and in the homozygous state in one individual with Neonatal Severe Hyperparathyroidism whose parents were both FHH-affected (e.g. Cole_2009, Vargas-Poussou_2016, Mouly_2020, Kurian_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence has shown that although the variant does not significantly alter the EC50 and results in only a mild reduction in the maximal Ca2+ response when studied in vitro, it results in a reduction in cell surface expression to 7% of normal, suggesting the variant has a damaging effect (e.g. Glaudo_2016, Leach_2012). Additionally, a variant affecting the same amino acid, c.2038C>T (p.Arg680Cys), has been classified as pathogenic, suggesting the Arg680 residue is important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 19179454, 11013439, 34993031, 22798347, 32347971, 26963950, 27666534). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=1)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 09, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226758.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP2, PP3, PM1, PM5, PS3
Number of individuals with the variant: 1
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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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Personalised medicines for familial hypercalcemia and hyperparathyroidism. | Josephs TM | Journal of molecular endocrinology | 2022 | PMID: 35318962 |
Severe Symptomatic Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia. | Kurian R | Cureus | 2021 | PMID: 34993031 |
Clinical characteristics of familial hypocalciuric hypercalcaemia type 1: A multicentre study of 77 adult patients. | Mouly C | Clinical endocrinology | 2020 | PMID: 32347971 |
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 |
Calcium-sensing receptor mutations and denaturing high performance liquid chromatography. | Cole DE | Journal of molecular endocrinology | 2009 | PMID: 19179454 |
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 |
Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. | Pollak MR | The Journal of clinical investigation | 1994 | PMID: 8132750 |
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Text-mined citations for rs773146939 ...
HelpRecord last updated Mar 05, 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.