3-122261715-G-A

Position:

chr3-122261715-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1PM2PM5PP2PP5_Very_StrongBP4

The NM_000388.4(CASR):c.680G>A(p.Arg227Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.15

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain 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-T is described in ClinVar as [Pathogenic]. Clinvar id is 8317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP5

Variant 3-122261715-G-A is Pathogenic according to our data. Variant chr3-122261715-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122261715-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.36536044). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.680G>A	p.Arg227Gln	missense_variant	4/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2 linkuse as main transcript	c.680G>A	p.Arg227Gln	missense_variant	4/7	1	NM_000388.4	P1	P41180-1
CASR	ENST00000498619.4 linkuse as main transcript	c.680G>A	p.Arg227Gln	missense_variant	4/7	1			P41180-2
CASR	ENST00000638421.1 linkuse as main transcript	c.680G>A	p.Arg227Gln	missense_variant	4/7	5		P1	P41180-1
CASR	ENST00000490131.7 linkuse as main transcript	c.680G>A	p.Arg227Gln	missense_variant	3/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250970

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The p.R227Q variant (also known as c.680G>A), located in coding exon 3 of the CASR gene, results from a G to A substitution at nucleotide position 680. The arginine at codon 227 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in two unrelated families with familial hypocalciuric hypercalcemia and segregated with affected individuals in these families (Chou YH et al. Am J Hum Genet, 1995 May;56:1075-9; Wystrychowski A et al. J Clin Endocrinol Metab, 2005 Feb;90:864-70). In vitro functional studies showed that cells expressing R227Q have decreased sensitivity to extracellular calcium concentrations (Wystrychowski A et al. J Clin Endocrinol Metab, 2005 Feb;90:864-70; Lu JY et al. J Pharmacol Exp Ther, 2009 Dec;331:775-86; Grant MP et al. Mol Endocrinol, 2012 Dec;26:2081-91; Glaudo M et al. Eur J Endocrinol, 2016 Nov;175:421-31). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

CASR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2023

The CASR c.680G>A variant is predicted to result in the amino acid substitution p.Arg227Gln. This variant has been reported in multiple individuals with familial hypocalciuric hypocalcemia (FHH) (Chou et al. 1995. PubMed ID: 7726161; Wystrychowski et al. 2005. PubMed ID: 15572418; Hannan et al. 2012. PubMed ID: 22422767; Vargas-Poussou et al. 2016. PubMed ID: 26963950). Additionally, several in vitro experimental studies have demonstrated that CASR protein carrying the p.Arg227Gln variant has impaired sensitivity to elevated extracellular calcium levels relative to wild type (Wystrychowski et al. 2005. PubMed ID: 15572418; White et al. 2009. PubMed ID: 19389809; Grant et al. 2012. PubMed ID: 23077345; Glaudo et al. 2016. PubMed ID: 27666534). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-121980562-G-A). Alternate nucleotide changes affecting the same amino acid (p.Arg227Leu, p.Arg227Gly) have also been reported as pathogenic in individuals with CASR-associated disease (Pearce et al. 1995. PubMed ID: 8675635; Glaudo et al. 2016. PubMed ID: 27666534). Taken together, the p.Arg227Gln variant is interpreted as pathogenic. -

Familial hypocalciuric hypercalcemia 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1995

- -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the CASR protein (p.Arg227Gln). This variant is present in population databases (rs28936684, gnomAD 0.0009%). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (FHH) (PMID: 1302026, 7726161, 15572418, 22422767, 26963950). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8331). 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: 19389809, 19759318, 23077345, 27666534). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 09, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 03, 2017

- -

Familial hypocalciuric hypercalcemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 24, 2022

Variant summary: CASR c.680G>A (p.Arg227Gln) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251070 control chromosomes (gnomAD and publication data). c.680G>A has been reported in the literature in multiple individuals affected with Familial Hypocalciuric Hypercalcemia (Chou_1992, Wystrychowski_2005, Glaudo_2016). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and results in reducing ability to induce ERK1/2 phosphorylation (Wystrychowski_2005, White_2009, Glaudo_2016). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.32

T;T;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

.;D;D;D

M_CAP

Benign

0.075

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.69

N;N;N;.

MutationTaster

Benign

0.96

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.15

.;.;N;N

REVEL

Uncertain

0.55

Sift

Benign

0.46

.;.;T;T

Sift4G

Benign

0.65

.;.;T;T

Polyphen

0.11

B;B;.;.

Vest4

0.49, 0.51

MutPred

0.64

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.94

MPC

1.4

ClinPred

0.66

GERP RS

4.4

Varity_R

0.39

gMVP

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over