rs886041154

Positions:

chr3-122254353-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.82

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:

CASR (HGNC:):

CASR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 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, 0.88

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	Protein	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.164C>T	p.Pro55Leu	missense_variant	2/7	ENST00000639785.2	NP_000379.3	P41180-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2 linkuse as main transcript	c.164C>T	p.Pro55Leu	missense_variant	2/7	1	NM_000388.4	ENSP00000491584.2		P41180-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727230

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

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). -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 19, 2024	PP1, PP2, PP3, PM2, PS3, PS4_moderate -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.5

H;H;H;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-8.2

.;.;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.018

.;.;D;D

Sift4G

Uncertain

0.0020

.;.;D;D

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

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

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