The R185Q variant has been reported in association with CASR-related disorders (Pollak et al., 1993; Bai et al., 1997; Reh et al., 2011). In vitro functional studies demonstrated that the R185Q variant results in substantially decreased signaling capacity (Bai et al., 1996; Leach et al., 2012). The R185Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R185Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000388.4(CASR):c.554G>A (p.Arg185Gln)
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.
(16)
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
16
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.554G>A (p.Arg185Gln)
Variation ID: 8314 Accession: VCV000008314.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q21.1 3: 122261589 (GRCh38) [ NCBI UCSC ] 3: 121980436 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 9, 2017 Oct 8, 2024 Sep 15, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000388.4:c.554G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000379.3:p.Arg185Gln missense NM_001178065.1:c.554G>A NM_001178065.2:c.554G>A NP_001171536.2:p.Arg185Gln missense NC_000003.12:g.122261589G>A NC_000003.11:g.121980436G>A NG_009058.1:g.82907G>A - Protein change
- R185Q
- Other names
- -
- Canonical SPDI
- NC_000003.12:122261588:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 |
2735 | 2758 | |
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) |
no assertion criteria provided
|
Jan 1, 1997 | RCV000008814.9 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 23, 2022 | RCV000008813.23 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2023 | RCV000412784.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 15, 2023 | RCV000627760.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 17, 2021 | RCV001804716.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 9, 2022 | RCV002496307.1 | |
|
CASR-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Mar 25, 2024 | RCV004554586.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypocalciuric hypercalcemia 1
Neonatal severe primary hyperparathyroidism Autosomal dominant hypocalcemia 1 Epilepsy, idiopathic generalized, susceptibility to, 8
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811752.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Feb 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016929.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Mar 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypocalciuric hypercalcemia 1
Affected status: yes
Allele origin:
maternal
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000590874.1
First in ClinVar: Aug 19, 2017 Last updated: Aug 19, 2017 |
Clinical Features:
hypercalcemia (present) , feeding intolerance (present) , emesis (present) , fussiness (present) , single umbilical artery (present)
Age: 0-9 years
Sex: male
Comment on evidence:
family history of Hypercalciuric Hypercalcemia, familial, type 1 (mother and maternal grandfather)
|
|
|
Pathogenic
(May 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490454.2
First in ClinVar: Jan 09, 2017 Last updated: Apr 17, 2019 |
Comment:
The R185Q variant has been reported in association with CASR-related disorders (Pollak et al., 1993; Bai et al., 1997; Reh et al., 2011). In vitro … (more)
The R185Q variant has been reported in association with CASR-related disorders (Pollak et al., 1993; Bai et al., 1997; Reh et al., 2011). In vitro functional studies demonstrated that the R185Q variant results in substantially decreased signaling capacity (Bai et al., 1996; Leach et al., 2012). The R185Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R185Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is pathogenic. (less)
|
|
|
Pathogenic
(Feb 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypocalciuric hypercalcemia 1
Affected status: yes
Allele origin:
unknown
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001427174.2
First in ClinVar: Aug 13, 2020 Last updated: Sep 18, 2020 |
Comment:
A heterozygous missense variant, NM_000388.3(CASR):c.554G>A, has been identified in exon 4 of 7 of the CASR gene. The variant is predicted to result in a … (more)
A heterozygous missense variant, NM_000388.3(CASR):c.554G>A, has been identified in exon 4 of 7 of the CASR gene. The variant is predicted to result in a minor amino acid change from arginine to glutamine at position 185 of the protein (NP_000379.2(CASR):p.(Arg185Gln)). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the ligand-binding functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in multiple patients (ClinVar). Additionally, studies showed altered protein function (Bai, M. et al., 1996; Glaudo, M. et al., 2016). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Clinical Features:
Hypercalcemia (present) , Hyperparathyroidism (present)
Secondary finding: no
|
|
|
Pathogenic
(Sep 29, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV001879547.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been reported both in individuals with familial hypocalciuric hypercalcemia and … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been reported both in individuals with familial hypocalciuric hypercalcemia and those with neonatal hyperparathyroidism. This variant appears to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 9011580, 21289269, 25091521). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in an attenuated response to calcium ion with an exerted dominant-negative effect on the wild-type receptor (PMID: 8702647, 22798347, 29848507, 19389809, 19759318, 17284438). Computational tools predict that this variant is damaging. (less)
|
|
|
Pathogenic
(Dec 17, 2021)
|
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: SCV002051184.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: CASR c.554G>A (p.Arg185Gln) 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.554G>A (p.Arg185Gln) results in a conservative amino acid change located in the Receptor, ligand binding region. (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251556 control chromosomes. c.554G>A has been reported in the literature in multiple individuals affected with Neonatal Severe Hyperparathyroidism (NSHPT) and/or Familial Hypocalciuric Hypercalcemia (FHH) (example, Obermannova_2009, Pollak_1993, Heath_1996, Bai_1997). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significantly higher EC50 in response to calcium agonists (example divalent calcium and trivalent cations such as Gadolimium) in addition to a dominant negative effect when co-expressed with wild-type CASR indicating that the primary abnormality in receptor function is in ligand binding (example Bai_1997). Six 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypocalciuric hypercalcemia 1
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV002540257.1
First in ClinVar: Jul 07, 2022 Last updated: Jul 07, 2022 |
Comment:
The CASR c.554G>A (p.Arg185Gln) missense variant results in the substitution of glutamine for arginine at amino acid position 185. Across a selection of the available … (more)
The CASR c.554G>A (p.Arg185Gln) missense variant results in the substitution of glutamine for arginine at amino acid position 185. Across a selection of the available literature, this variant has been reported in a heterozygous state in at least seven unrelated individuals with neonatal severe hyperparathyroidism (Bai et al. 1997; Obermannova et al. 2009; Reh et al. 2011; Gannon et al. 2014; Fisher et al. 2015; Glaudo et al. 2016). In two cases, the c.554G>A variant was presumed or confirmed de novo. The variant was also reported in a heterozygous state in a patient's father, who had elevated serum calcium. In addition, at least 14 individuals with the same variant were diagnosed with a familial hypocalciuric hypercalcemia phenotype and no neonatal symptoms (Glaudo et al. 2016). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. When expressed in HEK293 cells, the c.554G>A variant has been shown to disrupt trafficking to the plasma membrane (White et al. 2009) and to disrupts the receptor's calcium signaling when expressed alone or in conjunction with the wildtype receptor (Bai et al. 1997; Glaudo et al. 2016). This variant is located in the extracellular domain, and three-dimensional modeling indicates it clusters with other variants in a cleft that contains a calcium binding site (Hanan et al. 2012). This variant was identified in a de novo state. Based on the available evidence, the c.554G>A (p.Arg185Gln) variant is classified as pathogenic for familial hypocalciuric hypercalcemia. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypocalciuric hypercalcemia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
|
Wangler Lab, Baylor College of Medicine
Accession: SCV002587060.1
First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 |
Comment:
This missense CASR variant at c.554G>A (p.R185Q) was seen on exome through the Texome project (R01HG011795). This variant has been previously reported in individuals with … (more)
This missense CASR variant at c.554G>A (p.R185Q) was seen on exome through the Texome project (R01HG011795). This variant has been previously reported in individuals with Hypocalciuric hypercalcemia, type I and/or Hyperparathyroidism, neonatal (PMID: 7916660, 9011580, 21289269, 24203066, 27666534). Functional studies suggest this variant is functionally defective (PMID: 9011580, 12114500, 17284438) (PS3). This variant has not been observed in gnomAD (PM2). It is predicted to be deleterious by multiple computational models (CADD: 30.000)(PP3), and the evolutionary conservation of this residue is high. We classify this variant as pathogenic. (less)
Age: 0-9 years
Sex: female
|
|
|
Pathogenic
(Mar 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypocalciuric hypercalcemia 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003836261.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
|
Pathogenic
(Mar 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226753.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PP2, PP3, PM2_supporting, PM6, PS3, PS4
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Sep 15, 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: SCV000550968.9
First in ClinVar: Feb 25, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CASR function (PMID: 12095982, 12114500, 17284438, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CASR function (PMID: 12095982, 12114500, 17284438, 19759318, 22798347, 25091521). 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: 8314). This variant is also known as p.Arg186Glu. This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia or severe neonatal hyperparathyroidism (PMID: 7916660, 9011580, 18751724, 21289269, 22422767, 24203066, 25091521, 26161261). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 185 of the CASR protein (p.Arg185Gln). (less)
|
|
|
Pathogenic
(Jan 01, 1997)
|
no assertion criteria provided
Method: literature only
|
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029023.8
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In a large kindred (family N) with hypocalciuric hypercalcemia (HCC1; 145980) described previously by Marx et al. (1982) as family A, Pollak et al. (1993) … (more)
In a large kindred (family N) with hypocalciuric hypercalcemia (HCC1; 145980) described previously by Marx et al. (1982) as family A, Pollak et al. (1993) found by RNase A protection assay that affected individuals were heterozygous for a mutation in exon 3 of the CASR gene: a G-to-A transition, predicting an arginine-to-glutamic acid change at amino acid residue 186 (ARG186GLU). Brown et al. (1995) pointed out in their legend to Figure 2 that Pollak et al. (1993) used the amino acid numbering based on the bovine receptor sequence and that the mutation was inadvertently reported as arg to glu instead of arg to gln; the correct designation of the mutation is therefore arg185 to gln or R185Q. Bai et al. (1997) reported a de novo arg185-to-gln mutation in a female infant with neonatal hyperparathyroidism (NSHPT; 239200). The authors stated that the mutation may exert a strong dominant-negative effect on the function of the normal CASR, resulting in NHPT and unusually severe hypercalcemia. The severity of the initial clinical presentation was due to the secondary hyperparathyroidism brought on by gestation of a fetus with abnormal parathyroid set point for Ca(2+)-regulated PTH in a mother with normal calcium homeostasis. (less)
|
|
|
Pathogenic
(Jan 01, 1997)
|
no assertion criteria provided
Method: literature only
|
HYPERPARATHYROIDISM, NEONATAL SEVERE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029024.7
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In a large kindred (family N) with hypocalciuric hypercalcemia (HCC1; 145980) described previously by Marx et al. (1982) as family A, Pollak et al. (1993) … (more)
In a large kindred (family N) with hypocalciuric hypercalcemia (HCC1; 145980) described previously by Marx et al. (1982) as family A, Pollak et al. (1993) found by RNase A protection assay that affected individuals were heterozygous for a mutation in exon 3 of the CASR gene: a G-to-A transition, predicting an arginine-to-glutamic acid change at amino acid residue 186 (ARG186GLU). Brown et al. (1995) pointed out in their legend to Figure 2 that Pollak et al. (1993) used the amino acid numbering based on the bovine receptor sequence and that the mutation was inadvertently reported as arg to glu instead of arg to gln; the correct designation of the mutation is therefore arg185 to gln or R185Q. Bai et al. (1997) reported a de novo arg185-to-gln mutation in a female infant with neonatal hyperparathyroidism (NSHPT; 239200). The authors stated that the mutation may exert a strong dominant-negative effect on the function of the normal CASR, resulting in NHPT and unusually severe hypercalcemia. The severity of the initial clinical presentation was due to the secondary hyperparathyroidism brought on by gestation of a fetus with abnormal parathyroid set point for Ca(2+)-regulated PTH in a mother with normal calcium homeostasis. (less)
|
|
|
Pathogenic
(Mar 25, 2024)
|
no assertion criteria provided
Method: clinical testing
|
CASR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004118924.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The CASR c.554G>A variant is predicted to result in the amino acid substitution p.Arg185Gln. This variant has been reported in many individuals to be causative … (more)
The CASR c.554G>A variant is predicted to result in the amino acid substitution p.Arg185Gln. This variant has been reported in many individuals to be causative for familial hypocalciuric hypercalcemia or neonatal hyperparathyroidism (Pollak et al. 1993. PubMed ID: 7916660; Bai et al. 1997. PubMed ID: 9011580; Reh et al. 2011. PubMed ID: 21289269; Obermannova et al. 2008. PubMed ID: 18751724; Glaudo et al. 2016. PubMed ID: 27666534). Functional studies indicate this variant alters protein function (Zhang et al. 2002. PubMed ID: 12114500; Bai et al. 1997. PubMed ID: 9011580). To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Familial hypocalciuric hypercalcemia 1
Affected status: yes
Allele origin:
de novo
|
GenomeConnect - Brain Gene Registry
Accession: SCV003931154.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
Variant classified as Pathogenic and reported on 12-13-2021 by Illumina. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does … (more)
Variant classified as Pathogenic and reported on 12-13-2021 by Illumina. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Short stature (present) , Delayed puberty (present) , Abnormal muscle physiology (present) , Abnormal skeletal muscle morphology (present) , Abnormality of the musculature of the … (more)
Short stature (present) , Delayed puberty (present) , Abnormal muscle physiology (present) , Abnormal skeletal muscle morphology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Hypercholesterolemia (present) , Abnormality of the pancreas (present) , Abnormality of the liver (present) , Abnormal renal physiology (present) , Abnormality of urine homeostasis (present) , Gingivitis (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: male
Method: Genome Sequencing
Testing laboratory: Illumina Laboratory Services, Illumina
Date variant was reported to submitter: 2021-12-13
Testing laboratory interpretation: Pathogenic
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
A heterozygous missense variant, NM_000388.3(CASR):c.554G>A, has been identified in exon 4 of 7 of the CASR gene. The variant is predicted to result in a minor amino acid change from arginine to glutamine at position 185 of the protein (NP_000379.2(CASR):p.(Arg185Gln)). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the ligand-binding functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in multiple patients (ClinVar). Additionally, studies showed altered protein function (Bai, M. et al., 1996; Glaudo, M. et al., 2016). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been reported both in individuals with familial hypocalciuric hypercalcemia and those with neonatal hyperparathyroidism. This variant appears to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 9011580, 21289269, 25091521). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in an attenuated response to calcium ion with an exerted dominant-negative effect on the wild-type receptor (PMID: 8702647, 22798347, 29848507, 19389809, 19759318, 17284438). Computational tools predict that this variant is damaging.
Comment:
Variant summary: CASR c.554G>A (p.Arg185Gln) results in a conservative amino acid change located in the Receptor, ligand binding region. (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251556 control chromosomes. c.554G>A has been reported in the literature in multiple individuals affected with Neonatal Severe Hyperparathyroidism (NSHPT) and/or Familial Hypocalciuric Hypercalcemia (FHH) (example, Obermannova_2009, Pollak_1993, Heath_1996, Bai_1997). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significantly higher EC50 in response to calcium agonists (example divalent calcium and trivalent cations such as Gadolimium) in addition to a dominant negative effect when co-expressed with wild-type CASR indicating that the primary abnormality in receptor function is in ligand binding (example Bai_1997). Six 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The CASR c.554G>A (p.Arg185Gln) missense variant results in the substitution of glutamine for arginine at amino acid position 185. Across a selection of the available literature, this variant has been reported in a heterozygous state in at least seven unrelated individuals with neonatal severe hyperparathyroidism (Bai et al. 1997; Obermannova et al. 2009; Reh et al. 2011; Gannon et al. 2014; Fisher et al. 2015; Glaudo et al. 2016). In two cases, the c.554G>A variant was presumed or confirmed de novo. The variant was also reported in a heterozygous state in a patient's father, who had elevated serum calcium. In addition, at least 14 individuals with the same variant were diagnosed with a familial hypocalciuric hypercalcemia phenotype and no neonatal symptoms (Glaudo et al. 2016). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. When expressed in HEK293 cells, the c.554G>A variant has been shown to disrupt trafficking to the plasma membrane (White et al. 2009) and to disrupts the receptor's calcium signaling when expressed alone or in conjunction with the wildtype receptor (Bai et al. 1997; Glaudo et al. 2016). This variant is located in the extracellular domain, and three-dimensional modeling indicates it clusters with other variants in a cleft that contains a calcium binding site (Hanan et al. 2012). This variant was identified in a de novo state. Based on the available evidence, the c.554G>A (p.Arg185Gln) variant is classified as pathogenic for familial hypocalciuric hypercalcemia.
Comment:
This missense CASR variant at c.554G>A (p.R185Q) was seen on exome through the Texome project (R01HG011795). This variant has been previously reported in individuals with Hypocalciuric hypercalcemia, type I and/or Hyperparathyroidism, neonatal (PMID: 7916660, 9011580, 21289269, 24203066, 27666534). Functional studies suggest this variant is functionally defective (PMID: 9011580, 12114500, 17284438) (PS3). This variant has not been observed in gnomAD (PM2). It is predicted to be deleterious by multiple computational models (CADD: 30.000)(PP3), and the evolutionary conservation of this residue is high. We classify this variant as pathogenic.
Comment:
PP1, PP2, PP3, PM2_supporting, PM6, PS3, PS4
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CASR function (PMID: 12095982, 12114500, 17284438, 19759318, 22798347, 25091521). 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: 8314). This variant is also known as p.Arg186Glu. This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia or severe neonatal hyperparathyroidism (PMID: 7916660, 9011580, 18751724, 21289269, 22422767, 24203066, 25091521, 26161261). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 185 of the CASR protein (p.Arg185Gln).
Comment:
The CASR c.554G>A variant is predicted to result in the amino acid substitution p.Arg185Gln. This variant has been reported in many individuals to be causative for familial hypocalciuric hypercalcemia or neonatal hyperparathyroidism (Pollak et al. 1993. PubMed ID: 7916660; Bai et al. 1997. PubMed ID: 9011580; Reh et al. 2011. PubMed ID: 21289269; Obermannova et al. 2008. PubMed ID: 18751724; Glaudo et al. 2016. PubMed ID: 27666534). Functional studies indicate this variant alters protein function (Zhang et al. 2002. PubMed ID: 12114500; Bai et al. 1997. PubMed ID: 9011580). To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
Variant classified as Pathogenic and reported on 12-13-2021 by Illumina. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
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:
The R185Q variant has been reported in association with CASR-related disorders (Pollak et al., 1993; Bai et al., 1997; Reh et al., 2011). In vitro functional studies demonstrated that the R185Q variant results in substantially decreased signaling capacity (Bai et al., 1996; Leach et al., 2012). The R185Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R185Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is pathogenic.
Comment:
A heterozygous missense variant, NM_000388.3(CASR):c.554G>A, has been identified in exon 4 of 7 of the CASR gene. The variant is predicted to result in a minor amino acid change from arginine to glutamine at position 185 of the protein (NP_000379.2(CASR):p.(Arg185Gln)). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the ligand-binding functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in multiple patients (ClinVar). Additionally, studies showed altered protein function (Bai, M. et al., 1996; Glaudo, M. et al., 2016). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been reported both in individuals with familial hypocalciuric hypercalcemia and those with neonatal hyperparathyroidism. This variant appears to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 9011580, 21289269, 25091521). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in an attenuated response to calcium ion with an exerted dominant-negative effect on the wild-type receptor (PMID: 8702647, 22798347, 29848507, 19389809, 19759318, 17284438). Computational tools predict that this variant is damaging.
Comment:
Variant summary: CASR c.554G>A (p.Arg185Gln) results in a conservative amino acid change located in the Receptor, ligand binding region. (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251556 control chromosomes. c.554G>A has been reported in the literature in multiple individuals affected with Neonatal Severe Hyperparathyroidism (NSHPT) and/or Familial Hypocalciuric Hypercalcemia (FHH) (example, Obermannova_2009, Pollak_1993, Heath_1996, Bai_1997). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significantly higher EC50 in response to calcium agonists (example divalent calcium and trivalent cations such as Gadolimium) in addition to a dominant negative effect when co-expressed with wild-type CASR indicating that the primary abnormality in receptor function is in ligand binding (example Bai_1997). Six 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The CASR c.554G>A (p.Arg185Gln) missense variant results in the substitution of glutamine for arginine at amino acid position 185. Across a selection of the available literature, this variant has been reported in a heterozygous state in at least seven unrelated individuals with neonatal severe hyperparathyroidism (Bai et al. 1997; Obermannova et al. 2009; Reh et al. 2011; Gannon et al. 2014; Fisher et al. 2015; Glaudo et al. 2016). In two cases, the c.554G>A variant was presumed or confirmed de novo. The variant was also reported in a heterozygous state in a patient's father, who had elevated serum calcium. In addition, at least 14 individuals with the same variant were diagnosed with a familial hypocalciuric hypercalcemia phenotype and no neonatal symptoms (Glaudo et al. 2016). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. When expressed in HEK293 cells, the c.554G>A variant has been shown to disrupt trafficking to the plasma membrane (White et al. 2009) and to disrupts the receptor's calcium signaling when expressed alone or in conjunction with the wildtype receptor (Bai et al. 1997; Glaudo et al. 2016). This variant is located in the extracellular domain, and three-dimensional modeling indicates it clusters with other variants in a cleft that contains a calcium binding site (Hanan et al. 2012). This variant was identified in a de novo state. Based on the available evidence, the c.554G>A (p.Arg185Gln) variant is classified as pathogenic for familial hypocalciuric hypercalcemia.
Comment:
This missense CASR variant at c.554G>A (p.R185Q) was seen on exome through the Texome project (R01HG011795). This variant has been previously reported in individuals with Hypocalciuric hypercalcemia, type I and/or Hyperparathyroidism, neonatal (PMID: 7916660, 9011580, 21289269, 24203066, 27666534). Functional studies suggest this variant is functionally defective (PMID: 9011580, 12114500, 17284438) (PS3). This variant has not been observed in gnomAD (PM2). It is predicted to be deleterious by multiple computational models (CADD: 30.000)(PP3), and the evolutionary conservation of this residue is high. We classify this variant as pathogenic.
Comment:
PP1, PP2, PP3, PM2_supporting, PM6, PS3, PS4
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CASR function (PMID: 12095982, 12114500, 17284438, 19759318, 22798347, 25091521). 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: 8314). This variant is also known as p.Arg186Glu. This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia or severe neonatal hyperparathyroidism (PMID: 7916660, 9011580, 18751724, 21289269, 22422767, 24203066, 25091521, 26161261). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 185 of the CASR protein (p.Arg185Gln).
Comment:
The CASR c.554G>A variant is predicted to result in the amino acid substitution p.Arg185Gln. This variant has been reported in many individuals to be causative for familial hypocalciuric hypercalcemia or neonatal hyperparathyroidism (Pollak et al. 1993. PubMed ID: 7916660; Bai et al. 1997. PubMed ID: 9011580; Reh et al. 2011. PubMed ID: 21289269; Obermannova et al. 2008. PubMed ID: 18751724; Glaudo et al. 2016. PubMed ID: 27666534). Functional studies indicate this variant alters protein function (Zhang et al. 2002. PubMed ID: 12114500; Bai et al. 1997. PubMed ID: 9011580). To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
Variant classified as Pathogenic and reported on 12-13-2021 by Illumina. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway. | Bazúa-Valenti S | Journal of the American Society of Nephrology : JASN | 2018 | PMID: 29848507 |
| Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia. | Szalat A | Endocrine | 2017 | PMID: 28176280 |
| Associations of the calcium-sensing receptor gene CASR rs7652589 SNP with nephrolithiasis and secondary hyperparathyroidism in haemodialysis patients. | Grzegorzewska AE | Scientific reports | 2016 | PMID: 27739473 |
| Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype. | Glaudo M | European journal of endocrinology | 2016 | PMID: 27666534 |
| Successful treatment of neonatal severe hyperparathyroidism with cinacalcet in two patients. | Fisher MM | Endocrinology, diabetes & metabolism case reports | 2015 | PMID: 26161261 |
| The calcium-sensing receptor: A promising target for prevention of colorectal cancer. | Aggarwal A | Biochimica et biophysica acta | 2015 | PMID: 25701758 |
| Calcium-sensing receptor sequencing in 21 patients with idiopathic or familial parathyroid disorder: pitfalls and characterization of a novel I32 V loss-of-function mutation. | Szalat A | Endocrine | 2015 | PMID: 25091521 |
| Cinacalcet monotherapy in neonatal severe hyperparathyroidism: a case study and review. | Gannon AW | The Journal of clinical endocrinology and metabolism | 2014 | PMID: 24203066 |
| 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 |
| 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 |
| Neonatal hyperparathyroidism with a heterozygous calcium-sensing receptor (CASR) R185Q mutation: clinical benefit from cinacalcet. | Reh CM | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 21289269 |
| Effect of the calcimimetic R-568 [3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine] on correcting inactivating mutations in the human calcium-sensing receptor. | Lu JY | The Journal of pharmacology and experimental therapeutics | 2009 | PMID: 19759318 |
| Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants. | White E | Molecular endocrinology (Baltimore, Md.) | 2009 | PMID: 19389809 |
| Unusually severe phenotype of neonatal primary hyperparathyroidism due to a heterozygous inactivating mutation in the CASR gene. | Obermannova B | European journal of pediatrics | 2009 | PMID: 18751724 |
| Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. | Egbuna OI | Best practice & research. Clinical rheumatology | 2008 | PMID: 18328986 |
| Neonatal severe hyperparathyroidism associated with a novel de novo heterozygous R551K inactivating mutation and a heterozygous A986S polymorphism of the calcium-sensing receptor gene. | Tõke J | Clinical endocrinology | 2007 | PMID: 17555508 |
| Identification and dissection of Ca(2+)-binding sites in the extracellular domain of Ca(2+)-sensing receptor. | Huang Y | The Journal of biological chemistry | 2007 | PMID: 17478419 |
| Identification and functional characterization of a novel mutation in the calcium-sensing receptor gene in familial hypocalciuric hypercalcemia: modulation of clinical severity by vitamin D status. | Zajickova K | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17473068 |
| 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 |
| [Percutaneous tenotomy of achilles tendon in the treatment of congenital clubfeet--a preliminary report]. | Kowalczyk B | Chirurgia narzadow ruchu i ortopedia polska | 2004 | PMID: 15751724 |
| Functional deletion of the calcium-sensing receptor in a case of neonatal severe hyperparathyroidism. | Ward BK | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15292296 |
| Naturally occurring mutations of the extracellular Ca2+-sensing receptor: implications for its structure and function. | Hu J | Trends in endocrinology and metabolism: TEM | 2003 | PMID: 12890593 |
| L-phenylalanine and NPS R-467 synergistically potentiate the function of the extracellular calcium-sensing receptor through distinct sites. | Zhang Z | The Journal of biological chemistry | 2002 | PMID: 12114500 |
| Three adjacent serines in the extracellular domains of the CaR are required for L-amino acid-mediated potentiation of receptor function. | Zhang Z | The Journal of biological chemistry | 2002 | PMID: 12095982 |
| 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 |
| A large homozygous or heterozygous in-frame deletion within the calcium-sensing receptor's carboxylterminal cytoplasmic tail that causes autosomal dominant hypocalcemia. | Lienhardt A | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 10770217 |
| In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia. | Bai M | The Journal of clinical investigation | 1997 | PMID: 9011580 |
| Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor. | Bai M | The Journal of biological chemistry | 1996 | PMID: 8702647 |
| Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. | Heath H 3rd | The Journal of clinical endocrinology and metabolism | 1996 | PMID: 8636323 |
| Calcium-ion-sensing cell-surface receptors. | Brown EM | The New England journal of medicine | 1995 | PMID: 7791841 |
| Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia. | Chou YH | American journal of human genetics | 1995 | PMID: 7726161 |
| Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. | Pollak MR | Cell | 1993 | PMID: 7916660 |
| An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds. | Marx SJ | The New England journal of medicine | 1982 | PMID: 7054696 |
| A comparison of the abilities of typical neuroleptic agents and of thioridazine, clozapine, sulpiride and metoclopramide to antagonise the hyperactivity induced by dopamine applied intracerebrally to areas of the extrapyramidal and mesolimbic systems. | Costall B | European journal of pharmacology | 1976 | PMID: 791660 |
| click to load more click to collapse | ||||
Text-mined citations for rs104893689 ...
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 25, 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.