chr3-122257279-C-G

Variant names:

• chr3-122257279-C-G
• rs1553766262
• NM_000388.4:c.384C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1 PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_000388.4(CASR):​c.384C>G​(p.Phe128Leu) variant causes a missense change. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F128I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.08
• Publications: 0 publications found

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]

CASR Gene-Disease associations (from GenCC):

• autosomal dominant hypocalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, Labcorp Genetics (formerly Invitae)
• familial hypocalciuric hypercalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Illumina, Orphanet, Genomics England PanelApp
• neonatal severe primary hyperparathyroidism

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal dominant hypocalcemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, idiopathic generalized, susceptibility to, 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS1: Transcript NM_000388.4 (CASR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CASR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.1237 (above the threshold of 3.09). Trascript score misZ: 4.8257 (above the threshold of 3.09). GenCC associations: The gene is linked to neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia 1, epilepsy, autosomal dominant hypocalcemia, epilepsy, idiopathic generalized, susceptibility to, 8.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782
• PP5: Variant 3-122257279-C-G is Pathogenic according to our data. Variant chr3-122257279-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1454775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.384C>G	p.Phe128Leu	missense_variant	Exon 3 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.384C>G	p.Phe128Leu	missense_variant	Exon 3 of 7	1	NM_000388.4	ENSP00000491584.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis Pathogenic:1

May 20, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.384C>G (p.F128L) alteration is located in exon 3 (coding exon 2) of the CASR gene. This alteration results from a C to G substitution at nucleotide position 384, causing the phenylalanine (F) at amino acid position 128 to be replaced by a leucine (L). Based on the supporting evidence, this alteration is pathogenic for CASR-related hypocalcemia; however, the association of this alteration with neonatal hyperparathyroidism/CASR-related hypocalciuric hypercalcemia is unknown. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Two other alterations at the same codon, c.384C>A (p.F128L) and c.382T>C (p.F128L), have been detected in individuals with features consistent with CASR-related hypocalcemia (Pearce, 1996a; Raue, 2011) including one de novo occurrence (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Transient transfection of wildtype and CASR p.F128L mutant Ca2+ receptor (CaR) in HEK-293 cells demonstrated that CaR is active at lower concentrations of extracellular calcium in the mutant protein compared to wildtype, indicating gain of receptor function (Pearce, 1996b; Hauche, 2000). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

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

Jan 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 128 of the CASR protein (p.Phe128Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypocalcemia and hypoparathyroidism (PMID: 8813042, 21645025). It has also been observed to segregate with disease in related individuals. 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: "Possibly Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects CASR function (PMID: 8813042, 8878438, 17284438). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	-0.096	T
MutationAssessor	Benign	1.2	L;L;L;.
PhyloP100		6.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.85	.;.;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.11	.;.;T;T
Sift4G	Benign	0.53	.;.;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.68, 0.68
MutPred		0.74		Gain of catalytic residue at F128 (P = 0.1874);Gain of catalytic residue at F128 (P = 0.1874);Gain of catalytic residue at F128 (P = 0.1874);Gain of catalytic residue at F128 (P = 0.1874);
MVP		0.94
MPC		1.6
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.53
gMVP		0.77
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs1553766262; hg19: chr3-121976126;