3-122284317-T-G

Position:

• chr3-122284317-T-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000388.4(CASR):​c.2363T>G​(p.Phe788Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F788L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.02

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 19 ACMG points.

• PM1: In a helix (size 22) in uniprot entity CASR_HUMAN there are 6 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 chr3-122284316-T-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, 0.976
• PP5: Variant 3-122284317-T-G is Pathogenic according to our data. Variant chr3-122284317-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 8336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122284317-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.2363T>G	p.Phe788Cys	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.2363T>G	p.Phe788Cys	missense_variant	7/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.2393T>G	p.Phe798Cys	missense_variant	7/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.2363T>G	p.Phe788Cys	missense_variant	7/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.2132T>G	p.Phe711Cys	missense_variant	5/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant hypocalcemia 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -
Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Jul 18, 2018	This individual is heterozygous for the variant c.2363T>G p.(Phe788Cys) in the CASR gene. This variant has been reported multiple individuals with autosomal dominant hypoparathyroidism and hypocalcaemia (Watanabe et al 1998 J Clin Endocrinol Metab. 83: 2497-2502; Kinoshita et al 2014 J Clin Endocrinol Metab. 99: E363-E368). In vitro analyses showed gain-of-function of the CaSR protein as a result of the p.Phe788Cys substitution, similar to other CASR variants associated with autosomal dominant hypocalcaemia (Watanabe et al 1998; Kinoshita et al 2014). The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster suggest that this variant is likely to be pathogenic. This variant is considered to be pathogenic according to the ACMG guidelines. -

Nephrolithiasis/nephrocalcinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The c.2363T>G (p.F788C) alteration is located in exon 7 (coding exon 6) of the CASR gene. This alteration results from a T to G substitution at nucleotide position 2363, causing the phenylalanine (F) at amino acid position 788 to be replaced by a cysteine (C). Based on the available evidence, the CASR c.2363T>G (p.F788C) alteration is classified as pathogenic for autosomal dominant CASR-related hypocalcemia; however, it is unlikely to be causative of autosomal recessive neonatal hyperparathyroidism and autosomal dominant hypocalciuric hypercalcemia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with CASR-related hypocalcemia, including at least one de novo occurrence (Ali, 2023; Elston, 2022; Wang, 2019; Rossi, 2019; Kinoshita, 2014; Watanabe, 1998; Mora, 2006). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies showed that this variant increases the sensitivity to extracellular calcium (Watanabe, 1998; Hu, 2002; Kinoshita, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 01, 2022

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 788 of the CASR protein (p.Phe788Cys). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CASR function (PMID: 9661634, 17284438, 19389809, 24297799). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 8336). This missense change has been observed in individuals with autosomal dominant hypocalcemia (PMID: 9661634, 26323216). It has also been observed to segregate with disease in related individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.1	.;.;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0080	.;.;D;.
Sift4G	Uncertain	0.011	.;.;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.94
MutPred		0.86		.;.;Gain of helix (P = 0.062);.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.79
gMVP		0.92

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: rs104893701; hg19: chr3-122003164;