3-122257275-A-G

Variant names:

• chr3-122257275-A-G
• rs121909260
• NM_000388.4:c.380A>G

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.380A>G​(p.Glu127Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E127A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.57

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 region_of_interest Ligand-binding 1 (LB1) (size 166) in uniprot entity CASR_HUMAN there are 70 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 chr3-122257275-A-C 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, 0.778
• PP5: Variant 3-122257275-A-G is Pathogenic according to our data. Variant chr3-122257275-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122257275-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.380A>G	p.Glu127Gly	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.380A>G	p.Glu127Gly	missense_variant	Exon 3 of 7	1	NM_000388.4	ENSP00000491584.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727212

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

May 23, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E127G variant in the CASR gene has been reported previously in an individual with autosomal dominant hypocalcaemic hypercalciuria; however, familial segregation information, in vitro functional studies, and additional clinical information were not included (Hannan et al., 2012). The E127G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E127G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same residue (E127A, E127K) and in nearby residues have been reported in the Human Gene Mutation Database in association with CASR-related disorders (Pollak et al., 1994; Lienhardt et al., 2001; Stenson et al., 2014), supporting the functional importance of this region of the protein. The E127G variant is a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded. -

Familial hypocalciuric hypercalcemia Pathogenic:1

Dec 22, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CASR c.380A>G (p.Glu127Gly) results in a non-conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251394 control chromosomes. c.380A>G has been reported in the literature in an individual affected with Hypocalciuric Hypercalcemia (Hannan_2012). Additionally, two other amino acid changes (p.Glu127Ala and p.Glu127Lys) have been classified as pathogenic/likely pathogenic in ClinVar, supporting the function importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22422767). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.095	D
MutationAssessor	Benign	1.3	L;L;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.6	.;.;N;N
REVEL	Pathogenic	0.71
Sift	Benign	0.050	.;.;D;T
Sift4G	Benign	0.12	.;.;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.84, 0.81
MutPred		0.59		Loss of stability (P = 0.1638);Loss of stability (P = 0.1638);Loss of stability (P = 0.1638);Loss of stability (P = 0.1638);
MVP		0.90
MPC		1.0
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.33
gMVP		0.77

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: rs121909260; hg19: chr3-121976122;