ClinVar Genomic variation as it relates to human health
NM_000388.4(CASR):c.748G>A (p.Glu250Lys)
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.748G>A (p.Glu250Lys)
Variation ID: 196262 Accession: VCV000196262.53
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q21.1 3: 122261783 (GRCh38) [ NCBI UCSC ] 3: 121980630 (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 Oct 20, 2024 Aug 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000388.4:c.748G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000379.3:p.Glu250Lys missense NM_001178065.2:c.748G>A NP_001171536.2:p.Glu250Lys missense NC_000003.12:g.122261783G>A NC_000003.11:g.121980630G>A NG_009058.1:g.83101G>A - Protein change
- E250K
- Other names
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- Canonical SPDI
- NC_000003.12:122261782: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00152
Trans-Omics for Precision Medicine (TOPMed) 0.00152
The Genome Aggregation Database (gnomAD) 0.00163
Exome Aggregation Consortium (ExAC) 0.00184
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00269
- 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 | ||
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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 |
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. |
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Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000177056.18 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000295987.12 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000325278.12 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000331288.12 | |
Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2024 | RCV000513760.33 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000987311.12 | |
Benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001081445.15 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 16, 2020 | RCV002257478.8 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 19, 2022 | RCV002492770.8 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 9, 2018 | RCV004020102.1 |
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. |
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Likely benign
(Feb 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000512483.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Benign
(Jan 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001879548.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
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Likely benign
(May 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610066.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
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Likely benign
(Apr 19, 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: SCV002801182.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely benign
(Aug 15, 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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024944.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Benign
(Aug 02, 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: SCV004039476.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: CASR c.748G>A (p.Glu250Lys) results in a conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. … (more)
Variant summary: CASR c.748G>A (p.Glu250Lys) results in a conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251346 control chromosomes. The observed variant frequency is approximately 121.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia phenotype (1.3e-05), strongly suggesting that the variant is benign. c.748G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia and autosomal dominant hypocalcaemia with Hypercalciuria without strong evidence for causality (examples: Simonds_2002, Hannan_2012, Nissen_2007, Frank-Raue_2011). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Hannan_2012). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 22422767, 22192860, 11807402, 21521328). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Nov 09, 2018)
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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: SCV001188886.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Aug 01, 2024)
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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: SCV001154028.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
CASR: BP4
Number of individuals with the variant: 5
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Benign
(Feb 05, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000228873.5
First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(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: SCV001136575.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Apr 27, 2017)
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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: SCV000440070.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
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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: SCV000440069.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
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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: SCV000440068.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
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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
|
Illumina Laboratory Services, Illumina
Accession: SCV000440067.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Nov 16, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002531540.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Jan 31, 2024)
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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: SCV000284800.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930674.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971846.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely benign
(May 09, 2022)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV003839316.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
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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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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 |
Identification of rare and frequent variants of the CASR gene by high-resolution melting. | Nissen PH | Clinica chimica acta; international journal of clinical chemistry | 2012 | PMID: 22192860 |
Inactivating calcium-sensing receptor mutations in patients with primary hyperparathyroidism. | Frank-Raue K | Clinical endocrinology | 2011 | PMID: 21521328 |
Molecular genetic analysis of the calcium sensing receptor gene in patients clinically suspected to have familial hypocalciuric hypercalcemia: phenotypic variation and mutation spectrum in a Danish population. | Nissen PH | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17698911 |
Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. | Simonds WF | Medicine | 2002 | PMID: 11807402 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CASR | - | - | - | - |
Text-mined citations for rs62269092 ...
HelpRecord last updated Oct 27, 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.