rs104893689

chr3-122261589-G-Achr3-122261589-G-Cchr3-122261589-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000388.4(CASR):c.554G>A(p.Arg185Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R185L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 10.0

Genes affected

CASR (HGNC:1514): (calcium sensing receptor) The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CASR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 3-122261589-G-A is Pathogenic according to our data. Variant chr3-122261589-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122261589-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.554G>A	p.Arg185Gln	missense_variant	4/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.554G>A	p.Arg185Gln	missense_variant	4/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.554G>A	p.Arg185Gln	missense_variant	4/7	1
CASR	ENST00000638421.1	c.554G>A	p.Arg185Gln	missense_variant	4/7	5		P1
CASR	ENST00000490131.7	c.554G>A	p.Arg185Gln	missense_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypocalciuric hypercalcemia 1 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Mar 14, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wangler Lab, Baylor College of Medicine	-	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. -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	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/. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 04, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 10, 2021	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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 27, 2023	PP1, PP2, PP3, PM2_supporting, PM6, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 29, 2020	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. -

CASR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2023

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. -

Neonatal severe primary hyperparathyroidism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1997

- -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2023

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). -

Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 09, 2022

- -

Familial hypocalciuric hypercalcemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 17, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.1	M;M;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.84	D
Polyphen		1.0	D;D;.;.
Vest4		0.97, 0.98
MutPred		0.96		Gain of ubiquitination at K181 (P = 0.0566);Gain of ubiquitination at K181 (P = 0.0566);Gain of ubiquitination at K181 (P = 0.0566);Gain of ubiquitination at K181 (P = 0.0566);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104893689; hg19: chr3-121980436; COSMIC: COSV56137698; COSMIC: COSV56137698;