ClinVar Genomic variation as it relates to human health
NM_000388.4(CASR):c.848T>C (p.Ile283Thr)
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.
Pathogenic(2); Likely pathogenic(1); Uncertain significance(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000388.4(CASR):c.848T>C (p.Ile283Thr)
Variation ID: 410355 Accession: VCV000410355.51
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q21.1 3: 122261883 (GRCh38) [ NCBI UCSC ] 3: 121980730 (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 2, 2017 Oct 8, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000388.4:c.848T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000379.3:p.Ile283Thr missense NM_001178065.1:c.848T>C NM_001178065.2:c.848T>C NP_001171536.2:p.Ile283Thr missense NC_000003.12:g.122261883T>C NC_000003.11:g.121980730T>C NG_009058.1:g.83201T>C - Protein change
- I283T
- Other names
- p.Ile283Thr
- Canonical SPDI
- NC_000003.12:122261882:T:C
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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) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00013
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
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. |
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CASR | No evidence available | No evidence available |
GRCh38 GRCh37 |
2725 | 2748 |
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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Dec 28, 2023 | RCV000463689.18 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Mar 25, 2024 | RCV001030008.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV002268085.15 | |
CASR-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jul 5, 2024 | RCV004554781.2 |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 5, 2023 | RCV004022778.1 | |
See cases
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Uncertain significance (1) |
criteria provided, single submitter
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Mar 21, 2022 | RCV004584387.1 |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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May 4, 2023 | RCV000493534.33 |
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
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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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Uncertain significance
(Dec 28, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000550994.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 283 of the CASR protein (p.Ile283Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 283 of the CASR protein (p.Ile283Thr). This variant is present in population databases (rs142745096, gnomAD 0.02%). This missense change has been observed in individual(s) with primary hyperparathyroidism (PMID: 20164288). ClinVar contains an entry for this variant (Variation ID: 410355). 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: 20164288). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Nov 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223022.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: CASR c.848T>C (p.Ile283Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: CASR c.848T>C (p.Ile283Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia (0.0001 vs 0.005), allowing no conclusion about variant significance. c.848T>C has been reported in the literature in at least one heterozygous individual affected with primary hyperparathyroidism (e.g. Guarnieri_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypocalciuric Hypercalcemia. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g.Guarnieri_2010). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Apr 20, 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: SCV004226145.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP2, PS4_moderate
Number of individuals with the variant: 3
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Uncertain significance
(May 04, 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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Revvity Omics, Revvity
Accession: SCV004234949.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial hypocalciuric hypercalcemia 1
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806423.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Sep 15, 2015)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000582495.4
First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017 |
Comment:
The I283T missense variant in the CASR gene has been reported previously in association with a CASR-related disorder (Guarnieri et al., 2010). Functional analysis showed … (more)
The I283T missense variant in the CASR gene has been reported previously in association with a CASR-related disorder (Guarnieri et al., 2010). Functional analysis showed impaired maturation, cell surface expression, and signaling of the I283T mutant protein compared with wild type. We interpret the I283T variant as pathogenic. (less)
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Uncertain significance
(Dec 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Nephrolithiasis/nephrocalcinosis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001179071.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.I283T variant (also known as c.848T>C), located in coding exon 3 of the CASR gene, results from a T to C substitution at nucleotide … (more)
The p.I283T variant (also known as c.848T>C), located in coding exon 3 of the CASR gene, results from a T to C substitution at nucleotide position 848. The isoleucine at codon 283 is replaced by threonine, an amino acid with similar properties. This variant has been detected in an individual with primary hyperparathyroidism and reported to impair cell surface expression and signaling (Guarnieri V et al. J. Clin. Endocrinol. Metab., 2010 Apr;95:1819-29). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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see cases
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002499655.2
First in ClinVar: Apr 23, 2022 Last updated: Jul 07, 2024 |
Comment:
ACMG categories: PM2,PP3
Number of individuals with the variant: 1
Clinical Features:
Hypermagnesemia (present)
Age: 0-9 years
Sex: male
Tissue: blood
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Uncertain significance
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550875.6
First in ClinVar: Jul 28, 2022 Last updated: Aug 04, 2024 |
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250022.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Sep 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002771681.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jul 05, 2024)
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no assertion criteria provided
Method: clinical testing
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CASR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004742640.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The CASR c.848T>C variant is predicted to result in the amino acid substitution p.Ile283Thr. This variant was reported in a 56-year-old woman with primary hyperparathyroidism … (more)
The CASR c.848T>C variant is predicted to result in the amino acid substitution p.Ile283Thr. This variant was reported in a 56-year-old woman with primary hyperparathyroidism (PHPT); functional analysis showed that this variant impaired the protein maturation, cell surface expression, and signaling (Guarnieri et al. 2010. PubMed ID: 20164288) and in an individual with kidney stone disease (Table S1, Anderegg et al. 2023. https://www.medrxiv.org/content/10.1101/2023.07.23.23292924v2.full). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Nov 08, 2019)
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no assertion criteria provided
Method: clinical testing
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Familial hypocalciuric hypercalcemia 1
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV001192811.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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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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A Novel Mutation of the Calcium-Sensing Receptor Gene Causing Familial Hypocalciuric Hypercalcemia Complicates Medical Followup after Roux-en-Y Gastric Bypass: A Case Report and a Summary of Mutations Found in the Same Hospital Laboratory. | Carlsson ER | Case reports in endocrinology | 2019 | PMID: 30895164 |
Calcium-sensing receptor (CASR) mutations in hypercalcemic states: studies from a single endocrine clinic over three years. | Guarnieri V | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 20164288 |
Calcium-sensing receptor mutations and denaturing high performance liquid chromatography. | Cole DE | Journal of molecular endocrinology | 2009 | PMID: 19179454 |
Text-mined citations for rs142745096 ...
HelpRecord last updated Oct 08, 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.