rs104893689

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 10.0

Variant links:

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]

CASR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a region_of_interest Ligand-binding 1 (LB1) (size 166) in uniprot entity CASR_HUMAN there are 70 pathogenic changes around while only 0 benign (100%) in NM_000388.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CASR. . Gene score misZ 3.1237 (greater than the threshold 3.09). Trascript score misZ 4.8257 (greater than threshold 3.09). GenCC has associacion of gene with epilepsy, autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 1, epilepsy, idiopathic generalized, susceptibility to, 8, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1.

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	Protein	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.554G>A	p.Arg185Gln	missense_variant	4/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2 linkuse as main transcript	c.554G>A	p.Arg185Gln	missense_variant	4/7	1	NM_000388.4	ENSP00000491584	P1	P41180-1
CASR	ENST00000498619.4 linkuse as main transcript	c.554G>A	p.Arg185Gln	missense_variant	4/7	1		ENSP00000420194		P41180-2
CASR	ENST00000638421.1 linkuse as main transcript	c.554G>A	p.Arg185Gln	missense_variant	4/7	5		ENSP00000492190	P1	P41180-1
CASR	ENST00000490131.7 linkuse as main transcript	c.554G>A	p.Arg185Gln	missense_variant	3/5	5		ENSP00000418685

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypocalciuric hypercalcemia 1

Pathogenic:6Other:1

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	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. -
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	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Mar 14, 2016	- -

not provided

Pathogenic:4

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. -
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 -

CASR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2024

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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

3.1

M;M;M;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.9

.;.;D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Uncertain

0.0030

.;.;D;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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over