rs121909259

chr3-122261924-G-Achr3-122261924-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000388.4(CASR):c.889G>A(p.Glu297Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. E297D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 10.0

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-122261926-G-C is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, CASR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 3-122261924-G-A is Pathogenic according to our data. Variant chr3-122261924-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8313.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-122261924-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.889G>A	p.Glu297Lys	missense_variant	4/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.889G>A	p.Glu297Lys	missense_variant	4/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.889G>A	p.Glu297Lys	missense_variant	4/7	1
CASR	ENST00000638421.1	c.889G>A	p.Glu297Lys	missense_variant	4/7	5		P1
CASR	ENST00000490131.7	c.889G>A	p.Glu297Lys	missense_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461856 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

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: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Neonatal severe primary hyperparathyroidism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 30, 2006

- -

Familial hypocalciuric hypercalcemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 30, 2006

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 20, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 297 of the CASR protein (p.Glu297Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (FHH) and/or neonatal severe hyperparathyroidism (PMID: 7916660, 16642557, 19423559). It has also been observed to segregate with disease in related individuals. This variant is also known as E298K. ClinVar contains an entry for this variant (Variation ID: 8313). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 12095982, 12114500, 23077345, 27434672). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.4	M;M;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.86	D
Polyphen		1.0	D;D;.;.
Vest4		0.97, 0.96
MutPred		0.88		Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.98

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: rs121909259; hg19: chr3-121980771; COSMIC: COSV56137950; COSMIC: COSV56137950;