chr3-122257322-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000388.4(CASR):c.427G>A(p.Gly143Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G143E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

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 19 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 chr3-122257323-G-A 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, 0.956

PP5

Variant 3-122257322-G-A is Pathogenic according to our data. Variant chr3-122257322-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 237770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122257322-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4 link	c.427G>A	p.Gly143Arg	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.427G>A	p.Gly143Arg	missense_variant	Exon 3 of 7	1	NM_000388.4	ENSP00000491584.2		P41180-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251306

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727224

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis

Pathogenic:1

May 28, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G143R variant (also known as c.427G>A), located in coding exon 2 of the CASR gene, results from a G to A substitution at nucleotide position 427. The glycine at codon 143 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals diagnosed with hyperparathyroidism (Ambry internal data; Cole DE et al. J Mol Endocrinol, 2009 Apr;42:331-9; Mariathasan S et al. Clin Endocrinol (Oxf), 2020 Oct;93:409-418).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, the evidence for the gene-disease relationship is limited for pancreatitis and cancer predisposition; therefore, the clinical significance of this variant for CASR-related pancreatitis and cancer predisposition is unclear. Loss-of-function variants in CASR are known to cause familial hypocalciuric hypercalcemia (FHH1); however, such associations with CASR-related hypocalcemia (ADH1) have not been reported (Hannan F et al. Nat Rev Endocrinol. 2018 Dec 1; 15(1): 33–51). Based on the supporting evidence, this variant is likely pathogenic for FHH1; however, the association of this variant with ADH1 is unlikely. -

CASR-related disorder

Pathogenic:1

Mar 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CASR c.427G>A variant is predicted to result in the amino acid substitution p.Gly143Arg. The p.Gly143Arg variant has been reported to be causative for familial hypocalciuric hypercalcemia (Cole et al. 2009. PubMed ID: 19179454; Mouly et al. 2020. PubMed ID: 32347971). In addition, a different substitution of this same amino acid (p.Gly143Glu) has also been reported to be pathogenic (Zhang et al. 2002. PubMed ID: 12114500) and several functional studies indicate the p.Gly143 residue is important for normal protein function (Bai et al. 1996. PubMed ID: 8702647; Grant et al. 2012. PubMed ID: 23077345). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Pathogenic:1

Aug 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 143 of the CASR protein (p.Gly143Arg). This variant is present in population databases (rs769256610, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypocalciuric hypercalcemia (PMID: 19179454, 32347971, 32430905; Invitae). Invitae‚Äö√Ñ√¥s autosomal dominant CASR-related conditions clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this CASR variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 606,512 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 237770). 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. This variant disrupts the p.Gly143 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7726161, 8702647, 19389809, 23077345). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Nov 05, 2021

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Computational tools predict that this variant is damaging. -

Familial hypocalciuric hypercalcemia

Pathogenic:1

Aug 28, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CASR c.427G>A (p.Gly143Arg) results in a non-conservative amino acid change located in the Receptor, ligand binding region domain (IPR001828) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251306 control chromosomes. c.427G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (e.g. Cole_2009, Mouly_2020, Mariathasan_2020). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.428G>A,p.Gly143Glu), supporting the critical relevance of codon 143 to CASR protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19179454, 31189130, 32430905, 32347971, 34088669). ClinVar contains an entry for this variant (Variation ID: 237770). 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

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;D;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;H;H;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.6

.;.;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Pathogenic

0.0010

.;.;D;D

Polyphen

1.0

D;D;.;.

Vest4

1.0, 1.0

MutPred

0.95

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

0.98

MPC

1.7

ClinPred

1.0

GERP RS

5.8

Varity_R

0.99

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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