3-122284403-G-A

Position:

• chr3-122284403-G-A

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.2449G>A​(p.Val817Ile) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 15 ACMG points.

• PM1: In a helix (size 17) in uniprot entity CASR_HUMAN there are 9 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, 0.882
• PP5: Variant 3-122284403-G-A is Pathogenic according to our data. Variant chr3-122284403-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122284403-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.2449G>A	p.Val817Ile	missense_variant	7/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.2449G>A	p.Val817Ile	missense_variant	7/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.2479G>A	p.Val827Ile	missense_variant	7/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.2449G>A	p.Val817Ile	missense_variant	7/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.2218G>A	p.Val740Ile	missense_variant	5/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 71

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/283120 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2021	Published functional studies demonstrate V817I showed reduced cell surface expression compared to wild type, as well as reduced Ca2+ potency in intracellular Ca2+ mobilization and reduced ERK1/2 phosphorylation (Leach et al., 2012); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27746744, 19779033, 8675635, 17039419, 24111791, 22798347, 19389809, 8878438, 17284438, 11013439, 11762699, 12890593, 23372019) -

Hypertrophic cardiomyopathy;C0020437:Hypercalcemia;C0020599:Hypocalciuria;C0262587:Parathyroid gland adenoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 05, 2015

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2021

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. Experimental studies have shown that this missense change affects CASR function (PMID: 8878438, 17284438, 22798347, 23372019). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 374153). This missense change has been observed in individuals with familial hypocalciuric hypercalcemia (FHH) (PMID: 8675635). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 817 of the CASR protein (p.Val817Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 05, 2022

- -

Familial hypocalciuric hypercalcemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 25, 2023

Variant summary: CASR c.2449G>A (p.Val817Ile) results in a conservative amino acid change located in the receptor calcium binding region (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251330 control chromosomes (gnomAD). c.2449G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (examples: Pearce_ 1995 and Vargas-Poussou_ 2016). These data indicate that the variant is likely to be associated with disease. Multiple studies have shown this variant leads to reduced cell surface expression, reduced Ca2+ sensitivity and reduced ERK1/2 phosphorylation compared to wild type (examples: Pearce_1996, Hu_2005, Huang_2007, Leach_2013, White_2018). The following publications have been ascertained in the context of this evaluation (PMID: 8675635, 17284438, 8878438, 15591042, 19389809, 26963950, 23372019). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.5	L;L;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.94	.;.;N;N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.028	.;.;D;T
Sift4G	Pathogenic	0.0	.;.;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.91
MutPred		0.78		.;.;Loss of glycosylation at S830 (P = 0.2429);.;
MVP		0.97
MPC		1.4
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.43
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057518933; hg19: chr3-122003250; COSMIC: COSV56134004;