3-122283896-C-T

Position:

• chr3-122283896-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000388.4(CASR):​c.1942C>T​(p.Arg648Ter) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASR NM_000388.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.764

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 18 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 94 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-122283896-C-T is Pathogenic according to our data. Variant chr3-122283896-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122283896-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.1942C>T	p.Arg648Ter	stop_gained	7/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1942C>T	p.Arg648Ter	stop_gained	7/7	1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.1972C>T	p.Arg658Ter	stop_gained	7/7	1		ENSP00000420194
CASR	ENST00000638421.1	c.1942C>T	p.Arg648Ter	stop_gained	7/7	5		ENSP00000492190	P1
CASR	ENST00000490131.7	c.1711C>T	p.Arg571Ter	stop_gained	5/5	5		ENSP00000418685

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461464 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

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

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypocalciuric hypercalcemia 1 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute	Mar 08, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2004	- -

Nephrolithiasis/nephrocalcinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2019

The p.R648* pathogenic mutation (also known as c.1942C>T), located in coding exon 6 of the CASR gene, results from a C to T substitution at nucleotide position 1942. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation has been reported in a few individuals with familial hypocalciuric hypercalcemia and segregated with disease in one large family (Jap TS et al. J. Clin. Endocrinol. Metab., 2001 Jan;86:13-5; Yamauchi M et al. J. Bone Miner. Res., 2002 Dec;17:2174-82). This mutation was also confirmed in trans in conjunction with another nonsense variant in an infant with neonatal severe hyperparathyroidism (Ward BK et al. J. Clin. Endocrinol. Metab., 2004 Aug;89:3721-30). In HEK293 cells, this mutation showed no response to high calcium levels compared to wild type (Yamauchi M et al. J. Bone Miner. Res., 2002 Dec;17:2174-82; Ward BK et al. J. Clin. Endocrinol. Metab., 2004 Aug;89:3721-30; Nakamura A et al. J. Clin. Endocrinol. Metab., 2013 Oct;98:E1692-701). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Neonatal severe primary hyperparathyroidism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2004

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change creates a premature translational stop signal (p.Arg648*) in the CASR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 431 amino acid(s) of the CASR protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 11231970, 12469911, 31672324, 32347971). ClinVar contains an entry for this variant (Variation ID: 8341). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CASR function (PMID: 23966241). This variant disrupts a region of the CASR protein in which other variant(s) (p.Trp718*) have been determined to be pathogenic (PMID: 9395465, 18796518). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.80	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.97
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs104893705; hg19: chr3-122002743;