rs104893694

chr3-122257347-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000388.4(CASR):c.452C>T(p.Thr151Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,808 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T151R) 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: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.17

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 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 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 chr3-122257347-C-G is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, CASR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 3-122257347-C-T is Pathogenic according to our data. Variant chr3-122257347-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122257347-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.452C>T	p.Thr151Met	missense_variant	3/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.452C>T	p.Thr151Met	missense_variant	3/7	1	NM_000388.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727206

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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant hypocalcemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 10, 1996

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CASR function (PMID: 8813042, 8878438). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 8323). This missense change has been observed in individual(s) with hyperparathyroidism and hypocalcemia (PMID: 20501971, 22422767, 23186954). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 151 of the CASR protein (p.Thr151Met). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 16, 2020

DNA sequence analysis of the CASR gene demonstrated a sequence change, c.452C>T, in exon 3 that results in an amino acid change, p.Thr151Met. This sequence change is absent in the gnomAD population database. This sequence change has been reported to segregated with disease in a family with hypoparathyroidism (PMID: 8698326). The p.Thr151Met change affects a highly conserved amino acid residue located in the extracellular domain of the calcium sensing receptor (CASR) protein. Functional study shows p.Thr151Met is a gain-of-function variant, and it results in the activation of CASR at a lower than normal extracellular calcium (PMID: 8878438). Collectively these evidences indicate that, this p.Thr151Me variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	0.64	N;N;N;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.70	T
Polyphen		1.0	D;D;.;.
Vest4		0.85, 0.84
MutPred		0.74		Loss of glycosylation at S147 (P = 0.0102);Loss of glycosylation at S147 (P = 0.0102);Loss of glycosylation at S147 (P = 0.0102);Loss of glycosylation at S147 (P = 0.0102);
MVP		0.99
MPC		1.6
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.58
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs104893694; hg19: chr3-121976194; COSMIC: COSV56139296;