3-122282134-C-T

Variant names:

• chr3-122282134-C-T
• rs886041637
• NM_000388.4:c.1630C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000388.4(CASR):​c.1630C>T​(p.Arg544*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,086 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CASR NM_000388.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.33

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-122282134-C-T is Pathogenic according to our data. Variant chr3-122282134-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 280428.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.1630C>T	p.Arg544*	stop_gained	Exon 6 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1630C>T	p.Arg544*	stop_gained	Exon 6 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.1660C>T	p.Arg554*	stop_gained	Exon 6 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.1630C>T	p.Arg544*	stop_gained	Exon 6 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.1399C>T	p.Arg467*	stop_gained	Exon 4 of 5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000370 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant hypocalcemia 1 Pathogenic:1

Jul 19, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrolithiasis/nephrocalcinosis Pathogenic:1

Oct 18, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R544* pathogenic mutation (also known as c.1630C>T), located in coding exon 5 of the CASR gene, results from a C to T substitution at nucleotide position 1630. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration was identified in the homozygous state in multiple individuals diagnosed with severe neonatal hyperparathyroidism (Savas-Erdeve S et al. J Pediatr Endocrinol Metab, 2016 Sep;29:1103-10; Sorapipatcharoen K et al. J Paediatr Child Health, 2020 Jul;56:1144-1146). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Neonatal severe primary hyperparathyroidism Pathogenic:1

Feb 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CASR c.1630C>T (p.Arg544X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251494 control chromosomes. c.1630C>T has been reported in the literature in at-least one homozygous individual affected with Neonatal Severe Hyperparathyroidism and heterozygous parents had mild hypercalcemia (example: Savas-Erdeve_2016). These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27390877). ClinVar contains an entry for this variant (Variation ID: 280428). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Jul 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg544*) in the CASR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CASR are known to be pathogenic (PMID: 11807402, 14985373, 22422767). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of neonatal hyperparathyroidism and familial hypercalcemia hypocalciuria (PMID: 27390877, 31672324). ClinVar contains an entry for this variant (Variation ID: 280428). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jan 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27390877, 31672324, 24763815) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.75	D
Vest4		0.79
GERP RS		-1.3

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: rs886041637; hg19: chr3-122000981;