chr3-122261715-G-T

Variant names:

• chr3-122261715-G-T
• rs28936684
• NM_000388.4:c.680G>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_000388.4(CASR):​c.680G>T​(p.Arg227Leu) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R227Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.15

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 16 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 chr3-122261715-G-A is described in Lovd as [Pathogenic].
• 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 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, 0.761
• PP5: Variant 3-122261715-G-T is Pathogenic according to our data. Variant chr3-122261715-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 8317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122261715-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.680G>T	p.Arg227Leu	missense_variant	Exon 4 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.680G>T	p.Arg227Leu	missense_variant	Exon 4 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.680G>T	p.Arg227Leu	missense_variant	Exon 4 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.680G>T	p.Arg227Leu	missense_variant	Exon 4 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.680G>T	p.Arg227Leu	missense_variant	Exon 3 of 5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neonatal severe primary hyperparathyroidism Pathogenic:2

Feb 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 03, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CASR c.680G>T (p.Arg227Leu) results in a non-conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250970 control chromosomes (gnomAD). c.680G>T has been reported in the literature in an individual affected with Neonatal Hyperparathyroidism as a de novo occurrence (Pearce_1995), as well as in an individual affected with Familial Hypocalciuric Hypercalcemia (Veldeman_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in impaired MAPK response to extracellular calcium levels (Wystrychowski_2005). The following publications have been ascertained in the context of this evaluation (PMID: 8675635, 15572418, 32306059). ClinVar contains an entry for this variant (Variation ID: 8317). Based on the evidence outlined above, the variant was classified as pathogenic. -

CASR-related disorder Pathogenic:1

Jan 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CASR c.680G>T variant is predicted to result in the amino acid substitution p.Arg227Leu. This variant was first reported to occur de novo in a patient with neonatal hyperparathyroidism (NHPT) (Pearce et al 1995. PubMed ID: 8675635) and was also reported in an individual with familial hypocalciuric hypercalcemia (Vargas-Poussou et al. 2016. PubMed ID: 26963950). At PreventionGenetics, we have observed the c.680G>T variant in two unrelated individuals with features of familial hypocalciuric hypercalcemia (internal data). In addition, multiple functional studies demonstrated the inactivating effect of this substitution (Wystrychowski A et al 2004. PubMed ID: 15572418; Lu JY et al 2009. PubMed ID: 19759318; Glaudo M et al 2016. PubMed ID: 27666534). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

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

May 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.227 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1302026, 7726161, 15572418, 22422767, 26963950). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CASR function (PMID: 8878438, 15572418, 27666534). 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: 8317). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia, and neonatal hyperparathyroidism (PMID: 8675635, 26963950). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 227 of the CASR protein (p.Arg227Leu). -

not provided Pathogenic:1

Nov 21, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PM2, PM5, PS2_supporting, PS3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;.;.
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.73	N;N;N;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	.;.;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.12	.;.;T;T
Sift4G	Benign	0.44	.;.;T;T
Polyphen		0.22	B;B;.;.
Vest4		0.86, 0.85
MutPred		0.63		Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);
MVP		0.94
MPC		1.5
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.50
gMVP		0.84

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: rs28936684; hg19: chr3-121980562;