rs1202110240

Positions:

• chr3-122261694-G-A

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.659G>A​(p.Arg220Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 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 Likely 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.15

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, 0.85
• PP5: Variant 3-122261694-G-A is Pathogenic according to our data. Variant chr3-122261694-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122261694-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.659G>A	p.Arg220Gln	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.659G>A	p.Arg220Gln	missense_variant	4/7	1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.659G>A	p.Arg220Gln	missense_variant	4/7	1		ENSP00000420194
CASR	ENST00000638421.1	c.659G>A	p.Arg220Gln	missense_variant	4/7	5		ENSP00000492190	P1
CASR	ENST00000490131.7	c.659G>A	p.Arg220Gln	missense_variant	3/5	5		ENSP00000418685

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250814 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135528

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: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant hypocalcemia 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jan 30, 2024

- -

Familial hypocalciuric hypercalcemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute

Mar 08, 2024

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2023

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. ClinVar contains an entry for this variant (Variation ID: 448997). This missense change has been observed in individuals with familial hypocalciuric hypercalcaemia (PMID: 9039332, 20495831, 32347971). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 220 of the CASR protein (p.Arg220Gln). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg220 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10885494, 11889203, 22142470). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2017

The R220Q variant in the CASR gene has previously been reported in at least one individual with familial hypocalciuric hypercalcemia (Pearce et al., 1996). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R220Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Arginine 220 is highly conserved across species at this position within the extracellular domain and functional studies have suggested that it is important for ligand-receptor interactions (D'Souza-Li et al., 2002). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein tructure/function. Alternate missense variants in the same residue (R220W, R220P) have been reported in association with familial hypocalciuric hypercalcemia, supporting the functional importance of this region of the protein (D'Souza-Li et al., 2002; Hannan et al., 2012). Based on currently available evidence, R220Q is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.056	D
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	.;.;N;N
REVEL	Pathogenic	0.74
Sift	Benign	0.095	.;.;T;T
Sift4G	Benign	0.17	.;.;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.75, 0.75
MutPred		0.70		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		0.94
MPC		1.7
ClinPred		0.89	D
GERP RS		4.4
Varity_R		0.71
gMVP		0.79

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: rs1202110240; hg19: chr3-121980541; COSMIC: COSV56141759; COSMIC: COSV56141759;