Submissions for variant NM_000388.4(CASR):c.554G>A (p.Arg185Gln)

dbSNP: rs104893689

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412784	SCV000490454	pathogenic	not provided	2018-05-04	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000627760	SCV000550968	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-09-15	criteria provided, single submitter	clinical testing	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).
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000008813	SCV000590874	pathogenic	Familial hypocalciuric hypercalcemia 1	2016-03-14	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008813	SCV001427174	pathogenic	Familial hypocalciuric hypercalcemia 1	2019-02-04	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics Inc	RCV000412784	SCV001879547	pathogenic	not provided	2020-09-29	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000412784	SCV002016929	pathogenic	not provided	2021-02-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804716	SCV002051184	pathogenic	Familial hypocalciuric hypercalcemia	2021-12-17	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000008813	SCV002540257	pathogenic	Familial hypocalciuric hypercalcemia 1	2021-12-10	criteria provided, single submitter	clinical testing	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.
Wangler Lab, Baylor College of Medicine	RCV000008813	SCV002587060	pathogenic	Familial hypocalciuric hypercalcemia 1		criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002496307	SCV002811752	pathogenic	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2022-05-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000008813	SCV003836261	pathogenic	Familial hypocalciuric hypercalcemia 1	2022-03-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398473	SCV004118924	pathogenic	CASR-related condition	2023-05-23	criteria provided, single submitter	clinical testing	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 B et al 2008. PubMed ID: 18751724; Glaudo M et al 2016. PubMed ID: 27666534). Functional studies indicate this variant alters protein function (Zhang Z et al 2002. PubMed ID: 12114500; Bai M et al 1997. PubMed ID: 9011580). To our knowledge, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000412784	SCV004226753	pathogenic	not provided	2023-03-27	criteria provided, single submitter	clinical testing	PP1, PP2, PP3, PM2_supporting, PM6, PS3, PS4
OMIM	RCV000008813	SCV000029023	pathogenic	Familial hypocalciuric hypercalcemia 1	1997-01-01	no assertion criteria provided	literature only
OMIM	RCV000008814	SCV000029024	pathogenic	Neonatal severe primary hyperparathyroidism	1997-01-01	no assertion criteria provided	literature only
GenomeConnect - Brain Gene Registry	RCV000008813	SCV003931154	not provided	Familial hypocalciuric hypercalcemia 1		no assertion provided	phenotyping only	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/.