ClinVar Genomic variation as it relates to human health
NM_000388.4(CASR):c.2915C>T (p.Thr972Met)
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.
Uncertain significance(9); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000388.4(CASR):c.2915C>T (p.Thr972Met)
Variation ID: 342802 Accession: VCV000342802.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q21.1 3: 122284869 (GRCh38) [ NCBI UCSC ] 3: 122003716 (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 Dec 6, 2016 Aug 11, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000388.4:c.2915C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000379.3:p.Thr972Met missense NM_001178065.2:c.2945C>T NP_001171536.2:p.Thr982Met missense NC_000003.12:g.122284869C>T NC_000003.11:g.122003716C>T NG_009058.1:g.106187C>T - Protein change
- T972M, T982M
- Other names
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- Canonical SPDI
- NC_000003.12:122284868: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
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 | ||
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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
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. |
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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
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. |
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000288087.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000345436.12 | |
Benign (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000383567.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 7, 2023 | RCV000525899.16 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV000664401.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2020 | RCV000711038.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 18, 2024 | RCV004021880.2 |
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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Uncertain significance
(Jan 29, 2018)
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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
Accession: SCV000841358.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial hypocalciuric hypercalcemia 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136578.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Jan 13, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000440131.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant hypocalcemia 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000440132.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neonatal severe primary hyperparathyroidism
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000440133.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial isolated hypoparathyroidism
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000440134.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Uncertain significance
(Dec 21, 2020)
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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: SCV001986154.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate intermediate levels of glycosylated mature protein and reduced CaSR signaling activity (Mastromatteo 2014); In silico analysis supports that this missense variant … (more)
Published functional studies demonstrate intermediate levels of glycosylated mature protein and reduced CaSR signaling activity (Mastromatteo 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25292184, 26646938) (less)
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Uncertain significance
(Nov 07, 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: SCV000638059.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 972 of the CASR protein (p.Thr972Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 972 of the CASR protein (p.Thr972Met). This variant is present in population databases (rs200620134, gnomAD 0.009%). This missense change has been observed in individual(s) with an atypical presentation of familial benign hypocalciuric hypercalcemia (FHH) and/or hyperparathyroidism (PMID: 25292184, 26646938). ClinVar contains an entry for this variant (Variation ID: 342802). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CASR function (PMID: 25292184). 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
(Mar 18, 2024)
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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: SCV001177929.5
First in ClinVar: Mar 16, 2020 Last updated: Aug 11, 2024 |
Comment:
The p.T972M variant (also known as c.2915C>T), located in coding exon 6 of the CASR gene, results from a C to T substitution at nucleotide … (more)
The p.T972M variant (also known as c.2915C>T), located in coding exon 6 of the CASR gene, results from a C to T substitution at nucleotide position 2915. The threonine at codon 972 is replaced by methionine, an amino acid with similar properties. This variant was identified in an individual with hypercalcemia, hypercalciuria, and improperly normal parathyroid hormone levels (Mastromatteo E et al. BMC Endocr Disord, 2014 Oct;14:81). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, the evidence for the gene-disease relationship is limited for pancreatitis and cancer predisposition; therefore, the clinical significance of this variant for CASR-related pancreatitis and cancer predisposition is unclear. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 26, 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: SCV004807421.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jul 25, 2018)
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no assertion criteria provided
Method: literature only
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HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000788331.1
First in ClinVar: Jul 29, 2018 Last updated: Jul 29, 2018 |
Comment on evidence:
In a 68-year-old man with hypercalcemia, inappropriately normal PTH levels, hypercalciuria, and recurrent nephrolithiasis (HHC1; 145980), Mastromatteo et al. (2014) identified heterozygosity for a c.2915C-T … (more)
In a 68-year-old man with hypercalcemia, inappropriately normal PTH levels, hypercalciuria, and recurrent nephrolithiasis (HHC1; 145980), Mastromatteo et al. (2014) identified heterozygosity for a c.2915C-T transition in exon 7 of the CASR gene, resulting in a thr972-to-met (T972M) substitution in the cytoplasmic tail. Screening of the proband's 3 asymptomatic sons revealed 1 carrier, a 41-year-old man with an ionized calcium level at the upper limit of normal and normal PTH and urinary calcium levels. Functional evaluation demonstrated strong impairment of signaling activity of the mutant receptor compared to wildtype, even at higher Ca(2+) concentrations. The authors concluded that T972M represents an inactivating mutation of the CASR gene causing an atypical presentation of familial benign hypercalcemia with hypercalciuria. The variant was not present in the public CaSR or 1000 Genomes Project databases. (less)
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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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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 |
A novel mutation in calcium-sensing receptor gene associated to hypercalcemia and hypercalciuria. | Mastromatteo E | BMC endocrine disorders | 2014 | PMID: 25292184 |
Text-mined citations for rs200620134 ...
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.