chr3-122261693-C-T

Position:

• chr3-122261693-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000388.4(CASR):​c.658C>T​(p.Arg220Trp) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R220P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.69

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 17 ACMG points.

• PM1: In a helix (size 13) in uniprot entity CASR_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-122261694-G-C is described in Lovd as [Pathogenic].
• 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, 0.933
• PP5: Variant 3-122261693-C-T is Pathogenic according to our data. Variant chr3-122261693-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 431804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122261693-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.658C>T	p.Arg220Trp	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.658C>T	p.Arg220Trp	missense_variant	4/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.658C>T	p.Arg220Trp	missense_variant	4/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.658C>T	p.Arg220Trp	missense_variant	4/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.658C>T	p.Arg220Trp	missense_variant	3/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250820 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135540

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	The R220W missense change in the CASR gene has previously been reported in association with familial hypocalciuric hypercalcemia (FHH) (for examples, see D'Souza-Li et al., 2002; Fox et al., 2007; Festen-Spanjer et al., 2008; Rasmussen et al., 2011). Functional studies have suggested that Arginine at codon 220 is important for ligand-receptor interactions (D'Souza-Li et al., 2002). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R220Wvariant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and is located within the extracellular bilobed venus flytrap domain (Hannan et al., 2012). Missense variants at the same residue (R220P, R220Q) have been reported in the Human Gene Mutation Database in association with hypocalciuric hypercalcaemia, supporting the functional importance of this region of the protein (Pearce et al., 1996; Hannan et al., 2012). Based on the currently available evidence, we consider R220W to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 18, 2017	- -

Neonatal severe primary hyperparathyroidism Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Sep 07, 2021

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 220 of the CASR protein (p.Arg220Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 10885494, 11763315, 11889203, 17974727, 22142470, 22192860, 22422767). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 431804). An algorithm developed specifically for the CASR gene suggests that this missense change is likely to be deleterious (PMID: 19102677). Experimental studies have shown that this missense change affects CASR function (PMID: 1889203, 11763315). For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.97	.;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.1	M;M;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.7	.;.;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.023	.;.;D;D
Sift4G	Uncertain	0.053	.;.;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.94
MutPred		0.79		Gain of glycosylation at Y218 (P = 0.0031);Gain of glycosylation at Y218 (P = 0.0031);Gain of glycosylation at Y218 (P = 0.0031);Gain of glycosylation at Y218 (P = 0.0031);
MVP		0.97
MPC		1.6
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.80
gMVP		0.86

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: rs1482119762; hg19: chr3-121980540; COSMIC: COSV56136175; COSMIC: COSV56136175;