rs1553768108

Variant names:

• chr3-122275900-A-G
• rs1553768108
• NM_000388.4:c.1466A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000388.4(CASR):​c.1466A>G​(p.Tyr489Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.13

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.984
• PP5: Variant 3-122275900-A-G is Pathogenic according to our data. Variant chr3-122275900-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446985.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.1466A>G	p.Tyr489Cys	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.1466A>G	p.Tyr489Cys	missense_variant	Exon 5 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.1466A>G	p.Tyr489Cys	missense_variant	Exon 5 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.1466A>G	p.Tyr489Cys	missense_variant	Exon 5 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.1378-6213A>G		intron_variant	Intron 3 of 4	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 489 of the CASR protein (p.Tyr489Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hypercalcemia and/or hyperparathyroidism (Invitae). Invitae’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: 446985). 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. 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. -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 05, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;H
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.6	.;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.017	.;.;D
Sift4G	Pathogenic	0.0	.;.;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.86		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.93

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

Other links and lift over

dbSNP: rs1553768108; hg19: chr3-121994747;