3-122261549-A-G

Position:

• chr3-122261549-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000388.4(CASR):​c.514A>G​(p.Arg172Gly) variant causes a missense change. 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)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.60

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 15 ACMG points.

• PM1: In a helix (size 3) in uniprot entity CASR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CASR. . Gene score misZ 3.1237 (greater than the threshold 3.09). Trascript score misZ 4.8257 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.854
• PP5: Variant 3-122261549-A-G is Pathogenic according to our data. Variant chr3-122261549-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 379844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122261549-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.514A>G	p.Arg172Gly	missense_variant	4/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.514A>G	p.Arg172Gly	missense_variant	4/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.514A>G	p.Arg172Gly	missense_variant	4/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.514A>G	p.Arg172Gly	missense_variant	4/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.514A>G	p.Arg172Gly	missense_variant	3/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 05, 2023	PP1, PP2, PM1, PM2, PS3_supporting, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2015	The R172G missense variant in the CASR gene has been reported previously in association with calciumhomeostasis disorders (Nakamura et al., 2013). The R172G substitution was not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. Missense variants in nearby residues(S171N, L173F) have been seen at GeneDx and reported in the Human Gene Mutation Database in associationwith calcium homeostasis disorders (Stenson et al., 2014). Therefore, we interpret R172G as a pathogenic variant. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 27, 2019

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change results in reduced ERK1/2 phosphorylation in response to extracellular calcium (PMID: 23966241) and structural models predict this variant resides in the CASR calcium binding site and may disrupt dimer formation (PMID: 27434672, 22422767). This variant has been reported in several individuals with suspected hypocalciuric hypercalcemia (PMID: 23966241, 22422767) and has been reported to segregate with familial hypercalciuric hypercalcemia in several families (PMID: 20034274). ClinVar contains an entry for this variant (Variation ID: 379844). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 172 of the CASR protein (p.Arg172Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.3	L;L;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	.;.;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.15	.;.;T;T
Sift4G	Benign	0.34	.;.;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.95, 0.94
MutPred		0.73		Loss of stability (P = 0.0137);Loss of stability (P = 0.0137);Loss of stability (P = 0.0137);Loss of stability (P = 0.0137);
MVP		0.84
MPC		1.8
ClinPred		0.90	D
GERP RS		3.5
Varity_R		0.80
gMVP		0.88

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: rs201851934; hg19: chr3-121980396;