chr3-122257101-G-A

Position:

chr3-122257101-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_000388.4(CASR):c.206G>A(p.Arg69His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 8.14

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:

CASR (HGNC:):

CASR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a helix (size 17) in uniprot entity CASR_HUMAN there are 5 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, 0.89

PP5

Variant 3-122257101-G-A is Pathogenic according to our data. Variant chr3-122257101-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122257101-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.206G>A	p.Arg69His	missense_variant	3/7	ENST00000639785.2	NP_000379.3	P41180-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2 linkuse as main transcript	c.206G>A	p.Arg69His	missense_variant	3/7	1	NM_000388.4	ENSP00000491584.2		P41180-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251300

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135822

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2017	The R69H variant in the CASR gene has previously been reported in association with familial hypocalciuric hypercalcemia and neonatal severe primary hyperparathyroidism (Wilhelm-Bals et al., 2012; Wolf et al., 2014; Corrado et al., 2015; Murphy et al., 2016). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R69H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, R69H is a strong candidate for a pathogenic variant. However, the possibility that it may be a rare benign variant cannot be excluded. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2024	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features of familial hypocalciuric hypercalcemia and has also been reported homozygous in individuals with neonatal severe hyperparathyroidism. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Nephrolithiasis/nephrocalcinosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The p.R69H pathogenic mutation (also known as c.206G>A), located in coding exon 2 of the CASR gene, results from a G to A substitution at nucleotide position 206. The arginine at codon 69 is replaced by histidine, an amino acid with highly similar properties. This variant has been observed in multiple individual with a personal and/or family history that is consistent with familial hypocalciuric hypercalcemia (FHH1) and has been detected in both the homozygous state and compound heterozygous with another CASR variant in multiple patients with neonatal severe hyperparathyroidism (Wilhelm-Bals A et al. Pediatrics, 2012 Mar;129:e812-6; Wolf P et al. J Clin Endocrinol Metab, 2014 Sep;99:E1721-6; Corrado KR et al. J Bone Miner Res, 2015 Oct;30:1797-802; Murphy H et al. Eur J Med Genet, 2016 Apr;59:227-31). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Loss-of-function variants in CASR are known to cause familial hypocalciuric hypercalcemia (FHH1); however, such associations with CASR-related hypocalcemia (ADH1) have not been reported (Hannan F et al. Nat Rev Endocrinol. 2018 Dec 1; 15(1): 33–51). In addition, the evidence for the gene-disease relationship is limited for pancreatitis and cancer predisposition; therefore, the clinical significance of this variant for CASR-related pancreatitis and cancer predisposition is unclear. Based on the supporting evidence, this variant is pathogenic for FHH1; however, the association of this variant with ADH1 is unlikely. -

Familial hypocalciuric hypercalcemia 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Neonatal severe primary hyperparathyroidism

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 28, 2020

Variant summary: CASR c.206G>A (p.Arg69His) results in a non-conservative amino acid change located in the Receptor, ligand binding region domain (IPR001828) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251300 control chromosomes (gnomAD). c.206G>A has been reported in the literature in the homozygous or compound heterozygous state in individuals affected with Neonatal Severe Hyperparathyroidism (e.g. Wilhelm-Bals_2012, Corrado_2015, Murphy_2016), while it has also been reported in the heterozygous state in individuals affected with Familial Hypocalciuric Hypercalcemia (e.g. Wolf_2014, Corrado_2015, Vargas-Poussou_2016, Hureaux_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 69 of the CASR protein (p.Arg69His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with familial hypocalciuric hypercalcemia, primary hyperparathyroidism and neonatal primary hyperparathyroidism and/or seizures (PMID: 22331334, 24947037, 25828954, 26855056, 26963950, 31672324, 32761341, 33258288). ClinVar contains an entry for this variant (Variation ID: 35787). 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. This variant disrupts the p.Arg69 amino acid residue in CASR. Other variant(s) that disrupt this residue have been observed in individuals with CASR-related conditions (PMID: 24947037), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.9

L;L;L;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.1

.;.;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

.;.;D;D

Sift4G

Uncertain

0.0030

.;.;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.92, 0.91

MutPred

0.79

Loss of MoRF binding (P = 0.01);Loss of MoRF binding (P = 0.01);Loss of MoRF binding (P = 0.01);Loss of MoRF binding (P = 0.01);

MVP

0.98

MPC

1.8

ClinPred

0.99

GERP RS

5.0

Varity_R

0.83

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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