3-122275959-G-A

Position:

• chr3-122275959-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2 PP3_Strong PP5_Very_Strong

The NM_000388.4(CASR):​c.1525G>A​(p.Gly509Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.88

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 13 ACMG points.

• 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, 0.965
• PP5: Variant 3-122275959-G-A is Pathogenic according to our data. Variant chr3-122275959-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122275959-G-A is described in Lovd as [Pathogenic]. Variant chr3-122275959-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.1525G>A	p.Gly509Arg	missense_variant	5/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1525G>A	p.Gly509Arg	missense_variant	5/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.1525G>A	p.Gly509Arg	missense_variant	5/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.1525G>A	p.Gly509Arg	missense_variant	5/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.1378-6154G>A		intron_variant		5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251448 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461736 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727178

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2023

ClinVar contains an entry for this variant (Variation ID: 35778). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 509 of the CASR protein (p.Gly509Arg). This variant is present in population databases (rs193922423, gnomAD 0.003%). This missense change has been observed in individual(s) with hypocalciuric hypercalcemia and/or neonatal severe hyperparathyroidism (PMID: 2476381, 17698911, 31672324, 32638038; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 29, 2020

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 associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant caused expression of only the immature form of the protein and abrogates the responsiveness of the receptor to calcium (PMID: 32638038). Computational tools predict that this variant is damaging. -

Familial hypocalciuric hypercalcemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 29, 2024

Variant summary: CASR c.1525G>A (p.Gly509Arg) results in a non-conservative amino acid change in 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 7.9e-06 in 251636 control chromosomes (gnomAD). c.1525G>A has been reported in the literature in multiple individuals affected with Familial Hypocalciuric Hypercalcemia (Nissen_2007, Christensen_2008). 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. The following publications have been ascertained in the context of this evaluation (PMID: 17698911, 18410554). ClinVar contains an entry for this variant (Variation ID: 35778). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.6	H;H;H
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.3	.;.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;.;D
Sift4G	Pathogenic	0.0010	.;.;D
Polyphen		1.0	D;D;.
Vest4		1.0
MutPred		0.78		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs193922423; hg19: chr3-121994806; COSMIC: COSV99949608;