rs121909263

chr3-122257308-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.413C>T(p.Thr138Met) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T138A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr3-122257307-A-C is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, CASR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 3-122257308-C-T is Pathogenic according to our data. Variant chr3-122257308-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122257308-C-T is described in Lovd as [Pathogenic]. Variant chr3-122257308-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.413C>T	p.Thr138Met	missense_variant	3/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.413C>T	p.Thr138Met	missense_variant	3/7	1	NM_000388.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2023

The p.T138M pathogenic mutation (also known as c.413C>T), located in coding exon 2 of the CASR gene, results from a C to T substitution at nucleotide position 413. The threonine at codon 138 is replaced by methionine, an amino acid with similar properties. This alteration was identified in multiple individuals with familial hypocalciuric hypercalcemia (FHH) (D'Souza-Li L et al. J Clin Endocrinol Metab, 2002 Mar;87:1309-18; Alam S et al. Indian J Endocrinol Metab, 2021 Jan;25:462-465; Bernardor J et al. Front Pediatr, 2022 Aug;10:926986; Ambry internal data) and segregated with disease in one large family (Chou YH et al. Am J Hum Genet, 1995 May;56:1075-9). This alteration was also identified in the homozygous state in an individual diagnosed with neonatal severe hyperparathyroidism (NSHPT) (Bernardor J et al. Front Pediatr, 2022 Aug;10:926986). In one functional study, this alteration showed reduced CASR function when exposed to extracellular calcium (Bai M et al. J Biol Chem, 1996 Aug;271:19537-45). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

CASR-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2022

The CASR c.413C>T variant is predicted to result in the amino acid substitution p.Thr138Met. This variant has been reported to segregate with disease in two families with hypocalciuric hypercalcemia (Chou et al 1995. PubMed ID: 7726161; Mouly et al 2020. PubMed ID: 32347971). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Familial hypocalciuric hypercalcemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1995

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 138 of the CASR protein (p.Thr138Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant CASR-related conditions (PMID: 1302026, 7726161, 11889203, 22422767, 26963950, 32347971). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr139Met. ClinVar contains an entry for this variant (Variation ID: 8332). 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: 8702647, 21239511). 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. -

Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 19, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 07, 2023

PP1_strong, PP2, PM1_supporting, PM2_supporting, PS3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.3	L;L;L;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.82	D
Polyphen		1.0	D;D;.;.
Vest4		0.94, 0.91
MutPred		0.68		Loss of glycosylation at S137 (P = 0.0192);Loss of glycosylation at S137 (P = 0.0192);Loss of glycosylation at S137 (P = 0.0192);Loss of glycosylation at S137 (P = 0.0192);
MVP		0.96
MPC		1.6
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.49
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: rs121909263; hg19: chr3-121976155;