3-122284208-C-T

Variant names:

• chr3-122284208-C-T
• rs193922434
• NM_000388.4:c.2254C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000388.4(CASR):​c.2254C>T​(p.Arg752Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,726 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 2.74

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 7 ACMG points.

• PM1: In a topological_domain Extracellular (size 23) in uniprot entity CASR_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000388.4
• 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, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.2254C>T	p.Arg752Cys	missense_variant	Exon 7 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.2254C>T	p.Arg752Cys	missense_variant	Exon 7 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.2284C>T	p.Arg762Cys	missense_variant	Exon 7 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.2254C>T	p.Arg752Cys	missense_variant	Exon 7 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.2023C>T	p.Arg675Cys	missense_variant	Exon 5 of 5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461726 Hom.: 0 Cov.: 70 AF XY: 0.00 AC XY: 0 AN XY: 727176

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hypocalciuric hypercalcemia Pathogenic:1

Jan 10, 2025

Hormonlaboratory, Oslo University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary: The variant, CASR c2254C>T; p.(Arg752Cys) is classified as likely pathogenic for Familial Hypocalciuric Hypercalcemia (FHH) based on the following criteria: The missense variant is predicted to change a highly conserved amino acid. There is a large physico-chemical difference between the amino acids. In-silico prediction (REVEL) is supporting a damaging effect on protein function (PP3). Our laboratory has observed this variant in 6 individuals from 5 different families, tested for a phenotype consistant with FHH (PS4, PP4). This variant is not reported in gnomAD vs 2 (PM2-S). It has been reported in the literature in individuals affected with FHH (PMID: 22422767). The variant is reported 3 times in ClinVar as a variant of uncertain significance. Both overall constraint and local constraint metrics in gnomAD vs2 support the use of PP2. -

not specified Uncertain:1

Jan 22, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The variant, CASR c.2254C>T (p.Arg752Cys) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245378 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant c.2254C>T has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (Hannan_2012). However, this report does not provide unequivocal conclusions about association of the variant with Familial Hypocalciuric Hypercalcemia (FHH). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 752 of the CASR protein (p.Arg752Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 22422767). ClinVar contains an entry for this variant (Variation ID: 35790). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Jul 31, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22422767) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.97	.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.4	M;M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.6	.;.;D;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Uncertain	0.026	.;.;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.60
MutPred		0.61		.;.;Loss of disorder (P = 0.0071);.;
MVP		0.92
MPC		1.8
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.69
gMVP		0.67

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: rs193922434; hg19: chr3-122003055; COSMIC: COSV56141487;