rs886041154

chr3-122254353-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1 PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000388.4(CASR):c.164C>T(p.Pro55Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P55S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.82

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 19 ACMG points.

• PS1: Transcript NM_000388.4 (CASR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 410326
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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, 0.88
• PP5: Variant 3-122254353-C-T is Pathogenic according to our data. Variant chr3-122254353-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 279731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122254353-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.164C>T	p.Pro55Leu	missense_variant	2/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.164C>T	p.Pro55Leu	missense_variant	2/7	1	NM_000388.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461862 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727230

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 28, 2023	PP1, PP2, PP3, PM2_supporting, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2018	The P55L pathogenic variant in the CASR gene has been reported previously in association with familial hypocalciuric hypercalcemia (Pearce et al., 1995; Hannan et al., 2012). This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies demonstrate that this substitution reduces calcium ion binding affinity of the extracellular domain of the CASR protein and leads to abnormal moderation of calcium homeostasis (Pearce et al., 1996; White et al., 2009; Lu et al., 2009). We interpret P55L as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2022	This variant has been identified in multiple unrelated individuals with autosomal dominant hypocalciuric hypercalcemia and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8878438, 10468915, 11763315, 19759318, 8636323, 8675635). -

Nephrolithiasis/nephrocalcinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2022

The p.P55L pathogenic mutation (also known as c.164C>T), located in coding exon 1 of the CASR gene, results from a C to T substitution at nucleotide position 164. The proline at codon 55 is replaced by leucine, an amino acid with similar properties. This mutation has been reported in multiple unrelated individuals and families with familial hypocalciuric hypercalcemia (Pearce SH et al. J Clin Invest, 1995 Dec;96:2683-92; Heath H et al. J Clin Endocrinol Metab, 1996 Apr;81:1312-7; Cetani F et al. Clin Endocrinol (Oxf), 2003 Feb;58:199-206; Speer G et al. Exp Clin Endocrinol Diabetes, 2003 Dec;111:486-90; Guarnieri V et al. J Clin Endocrinol Metab, 2010 Apr;95:1819-29; Hannan FM et al. Hum Mol Genet, 2012 Jun;21:2768-78). In vitro studies showed that P55L reduces the ability of the calcium-sensing receptor to sense extracellular calcium (Pearce SH et al. J Clin Invest, 1996 Oct;98:1860-6; Heath H et al. J Clin Endocrinol Metab, 1996 Apr;81:1312-7; Lu JY et al. J Pharmacol Exp Ther, 2009 Dec;331:775-86). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypocalciuric hypercalcemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute

Mar 08, 2024

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 55 of the CASR protein (p.Pro55Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 8675635, 11763315, 12580936, 20164288, 22422767, 24947037). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279731). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 8878438, 19389809, 19759318). For these reasons, this variant has been classified as Pathogenic. -

Familial hypocalciuric hypercalcemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 15, 2022

Variant summary: CASR c.164C>T (p.Pro55Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250952 control chromosomes. c.164C>T has been widely reported in the literature in multiple individuals affected with Familial Hypocalciuric Hypercalcemia (example, Pearce_1995, Sumida_2022). 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 reduced responsiveness of the calcium receptor to ionic calcium levels consistent with a loss of function mechanism of disease (example, Pearce_1996). Three 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	0.96
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.5	H;H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
Polyphen		1.0	D;D;.;.
Vest4		0.94, 0.94
MutPred		0.46		Gain of glycosylation at S57 (P = 0.0158);Gain of glycosylation at S57 (P = 0.0158);Gain of glycosylation at S57 (P = 0.0158);Gain of glycosylation at S57 (P = 0.0158);
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.81
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886041154; hg19: chr3-121973200;