rs104893716

Variant names:

• chr3-122275828-G-A
• rs104893716
• NM_000388.4:c.1394G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-122275828-G-A
• chr3-122275828-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP2 PP3 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.84
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant hypocalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, Labcorp Genetics (formerly Invitae)
• familial hypocalciuric hypercalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Illumina, Orphanet, Genomics England PanelApp
• neonatal severe primary hyperparathyroidism

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal dominant hypocalcemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, idiopathic generalized, susceptibility to, 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• 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 ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 410348.
• 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 neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia 1, epilepsy, autosomal dominant hypocalcemia, epilepsy, idiopathic generalized, susceptibility to, 8.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 8352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.1394G>A	p.Arg465Gln	missense_variant	Exon 5 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1394G>A	p.Arg465Gln	missense_variant	Exon 5 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.1394G>A	p.Arg465Gln	missense_variant	Exon 5 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.1394G>A	p.Arg465Gln	missense_variant	Exon 5 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.1378-6285G>A		intron_variant	Intron 3 of 4	5		ENSP00000418685.2

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

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111406

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypocalciuric hypercalcemia 1 Pathogenic:2

Mar 08, 2024

Molecular Genetics Laboratory, Biobizkaia Health Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 14, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nephrolithiasis/nephrocalcinosis Pathogenic:1

Jun 03, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Mar 07, 2023

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 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
PhyloP100		6.8
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
Mutation Taster		=14/86	disease causing (ClinVar)

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

Other links and lift over

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