rs121909260

Positions:

• chr3-122257275-A-C
• chr3-122257275-A-G

Variant summary

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

The ENST00000639785.2(CASR):​c.380A>C​(p.Glu127Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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. E127G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR ENST00000639785.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in ENST00000639785.2
• 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-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.
• 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, 0.826
• PP5: Variant 3-122257275-A-C is Pathogenic according to our data. Variant chr3-122257275-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 8315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122257275-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.380A>C	p.Glu127Ala	missense_variant	3/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.380A>C	p.Glu127Ala	missense_variant	3/7	1	NM_000388.4	ENSP00000491584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant hypocalcemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1994

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 127 of the CASR protein (p.Glu127Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hypocalcemia (PMID: 7874174). It has also been observed to segregate with disease in related individuals. This variant is also known as Glu128Ala. ClinVar contains an entry for this variant (Variation ID: 8315). 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: 7874174, 8702647). 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

Apr 27, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2017

The E127A variant has been published previously in association with hypocalcaemia (Pollak et al., 1994). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). E127A 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. Functional studies have shown E127A to be a gain-of-function variant (Pollak et al., 1994; Young et al., 2015). Missense variants in the same codon (E127K/G) and in nearby residues (L123S, N124K, L125F/P, F128L, C129S/R/F/S/Y, C131S/Y/F/W) have been reported in the Human Gene Mutation Database in association with CASR-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.092	D
MutationAssessor	Benign	1.5	L;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.0	.;.;N;N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.019	.;.;D;D
Sift4G	Benign	0.078	.;.;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.76, 0.77
MutPred		0.61		Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);
MVP		0.91
MPC		1.6
ClinPred		0.93	D
GERP RS		5.8
Varity_R		0.38
gMVP		0.75

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;