rs104893694

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000388.4(CASR):c.452C>T(p.Thr151Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,808 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T151R) has been classified 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:5

Conservation

PhyloP100: 6.17

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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-122257347-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in the CASR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.1237 (above the threshold of 3.09). Trascript score misZ: 4.8257 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.887

PP5

Variant 3-122257347-C-T is Pathogenic according to our data. Variant chr3-122257347-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122257347-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4 link	c.452C>T	p.Thr151Met	missense_variant	Exon 3 of 7	ENST00000639785.2	NP_000379.3	P41180-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2 link	c.452C>T	p.Thr151Met	missense_variant	Exon 3 of 7	1	NM_000388.4	ENSP00000491584.2		P41180-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727206

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant hypocalcemia 1

Pathogenic:2

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene and are associated with CASR-related disease (OMIM). Truncating variants predicted to undergo nonsense-mediated decay, and missense variants with either a dominant negative or loss of function effect on protein function, have been reported to cause hypocalciuric hypercalcemia, type I (MIM#145980), and neonatal hyperparathyroidism (MIM#239200). Missense variants that have a gain of function effect on protein activity, have been reported to cause hypocalcemia, with or without Barrter syndrome (MIM#601198) (PMID: 22422767, PMID: 26646938, OMIM, Ward et al. (2006)). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive disease is caused by biallelic loss of function variants (PMID: 22422767, PMID: 26646938). (I) 0115 - Variants in this gene are known to have variable expressivity. Members of the same family have been reported to exhibit either hypercalcemia, hypocalciuric or hypercalciuric (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cleft between lobes 1 and 2 within the calcium binding site 1 (PMID: 22422767). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.Thr151Arg) has been described as pathogenic, and reported in several patients with hypocalcemia or hypoparathyroidism (LOVD, PMID: 20668040, PMID: 21645025). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in several unrelated families with hypoparathyroidism or hypocalcemic hypercalciuria (ClinVar, PMID: 8813042, PMID: 8698326, PMID: 22422767). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregated with disease in one large family with hypocalcaemia (PMID: 20501971). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. HEK293 cells transfected with this variant displayed maximal responses at lower calcium concentrations (PMID: 8813042). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Oct 10, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Sep 16, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the CASR gene demonstrated a sequence change, c.452C>T, in exon 3 that results in an amino acid change, p.Thr151Met. This sequence change is absent in the gnomAD population database. This sequence change has been reported to segregated with disease in a family with hypoparathyroidism (PMID: 8698326). The p.Thr151Met change affects a highly conserved amino acid residue located in the extracellular domain of the calcium sensing receptor (CASR) protein. Functional study shows p.Thr151Met is a gain-of-function variant, and it results in the activation of CASR at a lower than normal extracellular calcium (PMID: 8878438). Collectively these evidences indicate that, this p.Thr151Me variant is pathogenic. -

Feb 29, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple unrelated individuals with clinical features associated with hypocalcemia 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, 8813042, 35459864) -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Pathogenic:1

Jan 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CASR function (PMID: 8813042, 8878438). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 8323). This missense change has been observed in individual(s) with hyperparathyroidism and hypocalcemia (PMID: 20501971, 22422767, 23186954). 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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 151 of the CASR protein (p.Thr151Met). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;.;.

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

0.64

N;N;N;.

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.67

.;.;N;N

REVEL

Pathogenic

0.68

Sift

Benign

0.047

.;.;D;D

Sift4G

Benign

0.33

.;.;T;T

Polyphen

1.0

D;D;.;.

Vest4

0.85, 0.84

MutPred

0.74

Loss of glycosylation at S147 (P = 0.0102);Loss of glycosylation at S147 (P = 0.0102);Loss of glycosylation at S147 (P = 0.0102);Loss of glycosylation at S147 (P = 0.0102);

MVP

0.99

MPC

1.6

ClinPred

0.95

GERP RS

5.8

Varity_R

0.58

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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