rs104893716

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong

The NM_000388.4(CASR):​c.1394G>A​(p.Arg465Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,146 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465W) 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

7
5
7

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.84
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-122275827-C-T 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, 0.82
PP5
Variant 3-122275828-G-A is Pathogenic according to our data. Variant chr3-122275828-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122275828-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CASRNM_000388.4 linkuse as main transcriptc.1394G>A p.Arg465Gln missense_variant 5/7 ENST00000639785.2 NP_000379.3 P41180-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CASRENST00000639785.2 linkuse as main transcriptc.1394G>A p.Arg465Gln missense_variant 5/71 NM_000388.4 ENSP00000491584.2 P41180-1
CASRENST00000498619.4 linkuse as main transcriptc.1394G>A p.Arg465Gln missense_variant 5/71 ENSP00000420194.1 P41180-2
CASRENST00000638421.1 linkuse as main transcriptc.1394G>A p.Arg465Gln missense_variant 5/75 ENSP00000492190.1 P41180-1
CASRENST00000490131.7 linkuse as main transcriptc.1378-6285G>A intron_variant 5 ENSP00000418685.2 A0A1X7SBX3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461146
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726980
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial hypocalciuric hypercalcemia 1 Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 14, 2006- -
Pathogenic, no assertion criteria providedclinical testingMolecular Genetics Laboratory, Biobizkaia Health Research InstituteMar 08, 2024- -
Nephrolithiasis/nephrocalcinosis Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 03, 2024The p.R465Q variant (also known as c.1394G>A), located in coding exon 4 of the CASR gene, results from a G to A substitution at nucleotide position 1394. The arginine at codon 465 is replaced by glutamine, an amino acid with highly similar properties. This variant has been identified in individuals with hyperparathyroidism as well as individuals with familial hypocalciuric hypercalcemia (Leech C et al. Biochem. Biophys. Res. Commun., 2006 Apr;342:996-1002; Mayr B et al. Eur. J. Endocrinol., 2016 May;174:R189-208; Vargas-Poussou R et al. J. Clin. Endocrinol. Metab., 2016 05;101:2185-95; Szalat A et al. Endocrine, 2017 Mar;55:741-747Asla Q et al. Endocrine, 2024 Mar;83:747-756; García-Castaño A et al. Front Endocrinol (Lausanne), 2024 Mar;15:1297614). 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 the supporting evidence, this variant is likely pathogenic for FHH1; however, the association of this variant with ADH1 is unlikely. -
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 11, 2023This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 465 of the CASR protein (p.Arg465Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with benign familial hypocalciuric hypercalcemia (PMID: 16598859, 26646938, 26963950, 28176280, 30407919; Invitae). ClinVar contains an entry for this variant (Variation ID: 8352). 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 tolerated. Experimental studies have shown that this missense change affects CASR function (PMID: 16598859). 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: 20164288, 29026550, 31672324; Invitae). 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. -
Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 30, 2024- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsMar 07, 2023This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant hypocalciuric hypercalcemia. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. 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: 16598859) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
T;T;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
.;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.82
D;D;D
MetaSVM
Uncertain
0.16
D
MutationAssessor
Benign
1.5
L;L;L
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.23
.;.;N
REVEL
Pathogenic
0.67
Sift
Benign
0.51
.;.;T
Sift4G
Benign
0.42
.;.;T
Polyphen
1.0
D;D;.
Vest4
0.86
MutPred
0.70
Gain of ubiquitination at K462 (P = 0.0768);Gain of ubiquitination at K462 (P = 0.0768);Gain of ubiquitination at K462 (P = 0.0768);
MVP
0.99
MPC
0.80
ClinPred
0.90
D
GERP RS
5.7
Varity_R
0.61
gMVP
0.70

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.

Other links and lift over

dbSNP: rs104893716; hg19: chr3-121994675; COSMIC: COSV99949243; API