3-122275827-C-T

Position:

chr3-122275827-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP2PP3_ModeratePP5

The NM_000388.4(CASR):c.1393C>T(p.Arg465Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,062 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 3.17

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 Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a helix (size 8) in uniprot entity CASR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000388.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-122275828-G-A is described in Lovd as [Pathogenic].

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, 0.901

PP5

Variant 3-122275827-C-T is Pathogenic according to our data. Variant chr3-122275827-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410348.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=5}. Variant chr3-122275827-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.1393C>T	p.Arg465Trp	missense_variant	5/7	ENST00000639785.2	NP_000379.3	P41180-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CASR	ENST00000639785.2 linkuse as main transcript	c.1393C>T	p.Arg465Trp	missense_variant	5/7	1	NM_000388.4	ENSP00000491584.2	P41180-1
CASR	ENST00000498619.4 linkuse as main transcript	c.1393C>T	p.Arg465Trp	missense_variant	5/7	1		ENSP00000420194.1	P41180-2
CASR	ENST00000638421.1 linkuse as main transcript	c.1393C>T	p.Arg465Trp	missense_variant	5/7	5		ENSP00000492190.1	P41180-1
CASR	ENST00000490131.7 linkuse as main transcript	c.1378-6286C>T		intron_variant		5		ENSP00000418685.2	A0A1X7SBX3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251282

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460846

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 13, 2024	PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 13, 2018	The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 04, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 465 of the CASR protein (p.Arg465Trp). This variant is present in population databases (rs751217000, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of familial hypocalciuric hypercalcemia (FHH) (PMID: 20164288, 29026550, 31672324, 32347971; Invitae). ClinVar contains an entry for this variant (Variation ID: 410348). 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: 20164288). This variant disrupts the p.Arg465 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16598859, 26646938, 26963950, 28176280, 30407919; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Familial hypocalciuric hypercalcemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 11, 2023

Variant summary: CASR c.1393C>T (p.Arg465Trp) results in a non-conservative amino acid change located in the ligand binding region (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 1.2e-05 in 251282 control chromosomes (gnomAD). c.1393C>T has been reported in the literature in the heterozygous state in multiple individuals affected with Familial Hypocalciuric Hypercalcemia, but often without segregation data (e.g. Guarnieri_2010, Vargas-Poussou_2016, Hureaux_2019, Mouly_2020). It has also been reported as a homozygous genotype in a woman with no family history of calcium distrubances who was asymptomatic until during her second pregnancy, but whose two heterozygous daughters were affected (Maltese_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant was associated with reduced maturation, cell surface expression, and cell signaling compared to the wild-type protein, however, it does not allow strong conclusions about the variant effect (Guarnieri_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20164288, 29026550, 32347971, 26963950, 31672324). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Epilepsy, idiopathic generalized, susceptibility to, 8

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

DASA

Feb 05, 2022

The c.1393C>T;p.(Arg465Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 20164288) - PS4_supporting. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 29026550) - PS3_supporting. The variant is present at low allele frequencies population databases (rs751217000 – gnomAD 0.00006570%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID: 8352 - c.1394G>A (p.Arg465Gln)) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 29026550) - PP1_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Nephrolithiasis/nephrocalcinosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The p.R465W variant (also known as c.1393C>T), located in coding exon 4 of the CASR gene, results from a C to T substitution at nucleotide position 1393. The arginine at codon 465 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been identified in individuals with hypercalcemia and inappropriately normal parathyroid hormone levels; however, if has also been identified in first degree relatives without hypercalcemia (Guarnieri V et al. J. Clin. Endocrinol. Metab., 2010 Apr;95:1819-29; Maltese G et al. Clin Case Rep, 2017 10;5:1587-1590). This variant has also been reported in additional familial hypocalciuric hypercalcemia cohorts (Hureaux M et al. Kidney Int, 2019 Dec;96:1408-1416; Mouly C et al. Clin Endocrinol (Oxf), 2020 Sep;93:248-260). In HEK293 cells, this variant was impaired relative to the wild type CASR with respect to maturation, cell surface expression, and signaling (Guarnieri V et al. J. Clin. Endocrinol. Metab., 2010 Apr;95:1819-29). 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. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

D;D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.1

M;M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-4.3

.;.;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

.;.;D

Sift4G

Pathogenic

0.0010

.;.;D

Polyphen

1.0

D;D;.

Vest4

0.98

MutPred

0.77

Gain of ubiquitination at K462 (P = 0.0482);Gain of ubiquitination at K462 (P = 0.0482);Gain of ubiquitination at K462 (P = 0.0482);

MVP

0.99

MPC

1.6

ClinPred

0.99

GERP RS

5.7

Varity_R

0.67

gMVP

0.83

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