rs1553768972

Positions:

• chr3-122283923-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000639785.2(CASR):​c.1972del​(p.Leu658CysfsTer40) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR ENST00000639785.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 153 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-122283923-TC-T is Pathogenic according to our data. Variant chr3-122283923-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 463917.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.1972del	p.Leu658CysfsTer40	frameshift_variant	7/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1972del	p.Leu658CysfsTer40	frameshift_variant	7/7	1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.2002del	p.Leu668CysfsTer40	frameshift_variant	7/7	1		ENSP00000420194
CASR	ENST00000638421.1	c.1972del	p.Leu658CysfsTer40	frameshift_variant	7/7	5		ENSP00000492190	P1
CASR	ENST00000490131.7	c.1741del	p.Leu581CysfsTer40	frameshift_variant	5/5	5		ENSP00000418685

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 24, 2019

This variant is not present in population databases (ExAC no frequency). This variant removes the last four transmembrane domains of the CASR protein. Experimental data has shown that similar truncated proteins lacking the last two or four transmembrane domains are not properly glycosylated, do not localize to the cell surface, and have an impaired response to extracellular calcium (PMID: 9395465). In addition, a different truncation downstream of this variant (p.W718X) has been determined to be pathogenic and has been reported in an individual with familial hypocalciuric hypercalcemia (FHH) (PMID: 18796518). These data suggest that deletion of this region of the CASR protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with CASR-related conditions. ClinVar contains an entry for this variant (Variation ID: 463917). This sequence change results in a premature translational stop signal in the CASR gene (p.Leu658Cysfs*40). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 421 amino acids of the CASR protein. -

Computational scores

Source: dbNSFP v4.3

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: rs1553768972; hg19: chr3-122002770;