3-122257308-C-T

Variant names:

• chr3-122257308-C-T
• rs121909263
• NM_000388.4:c.413C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 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. T138R) 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:7
• Conservation: PhyloP100: 6.17
• Publications: 9 publications found

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]

CASR Gene-Disease associations (from GenCC):

• autosomal dominant hypocalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, Labcorp Genetics (formerly Invitae)
• familial hypocalciuric hypercalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Illumina, Orphanet, Genomics England PanelApp
• neonatal severe primary hyperparathyroidism

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal dominant hypocalcemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, idiopathic generalized, susceptibility to, 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 15 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, 13 uncertain in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• 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 neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia 1, epilepsy, autosomal dominant hypocalcemia, epilepsy, idiopathic generalized, susceptibility to, 8.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 8332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000388.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	NM_000388.4	MANE Select	c.413C>T	p.Thr138Met	missense	Exon 3 of 7	NP_000379.3
	CASR	NM_001178065.2		c.413C>T	p.Thr138Met	missense	Exon 3 of 7	NP_001171536.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.413C>T	p.Thr138Met	missense	Exon 3 of 7	ENSP00000491584.2
	CASR	ENST00000498619.4	TSL:1	c.413C>T	p.Thr138Met	missense	Exon 3 of 7	ENSP00000420194.1
	CASR	ENST00000638421.1	TSL:5	c.413C>T	p.Thr138Met	missense	Exon 3 of 7	ENSP00000492190.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis Pathogenic:1

Sep 16, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 disorder Pathogenic:1

Nov 21, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 familial hypocalciuric hypercalcemia (PMID: 1302026, 7726161, 11889203, 22422767, 26963950, 32347971). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this CASR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 606,512 individuals referred to our laboratory for CASR testing. 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). 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

Oct 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Mar 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP2, PM1_supporting, PM2_supporting, PS3, PS4_moderate

Familial hypocalciuric hypercalcemia Pathogenic:1

Jun 18, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CASR c.413C>T (p.Thr138Met) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251408 control chromosomes. c.413C>T has been observed in multiple individuals affected with Familial Hypocalciuric Hypercalcemia (example, Alam_2021, Bai_1996, Chou_1992, 1995, Dsouza-Li_2002). It has also been reported at a homozygous state in an individual with Neonatal Severe Hyperparathyroidism (Bernardor_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced normal activity of CASR in HEK293 cells (Bai_1996). The following publications have been ascertained in the context of this evaluation (PMID: 35300448, 8702647, 7726161, 1302026, 11889203, 36090548). ClinVar contains an entry for this variant (Variation ID: 8332). Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.3	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.30	N
REVEL	Pathogenic	0.68
Sift	Benign	0.046	D
Sift4G	Benign	0.066	T
Polyphen		1.0	D
Vest4		0.94
MutPred		0.68		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909263; hg19: chr3-121976155; COSMIC: COSV108808729;