NM_000388.4(CASR):c.1942C>T (p.Arg648Ter) AND multiple conditions

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003764537.1

Allele description

NM_000388.4(CASR):c.1942C>T (p.Arg648Ter)

Gene:

CASR:calcium sensing receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q21.1

Genomic location:

Preferred name:

NM_000388.4(CASR):c.1942C>T (p.Arg648Ter)

HGVS:

NC_000003.12:g.122283896C>T
NG_009058.1:g.105214C>T
NM_000388.4:c.1942C>TMANE SELECT
NM_001178065.2:c.1972C>T
NP_000379.3:p.Arg648Ter
NP_001171536.2:p.Arg658Ter
NC_000003.11:g.122002743C>T
NM_000388.3:c.1942C>T

Protein change:

R648*; ARG648TER

Links:

OMIM: 601199.0032; dbSNP: rs104893705

NCBI 1000 Genomes Browser:

rs104893705

Molecular consequence:

NM_000388.4:c.1942C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001178065.2:c.1972C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Familial hypocalciuric hypercalcemia (FHH)
Synonyms:: Familial benign hypercalcemia
Identifiers:: MONDO: MONDO:0018458; MedGen: C1809471; OMIM: PS145980

Name:: Autosomal dominant hypocalcemia 1 (HYPOC1)
Synonyms:: HYPOCALCEMIA, FAMILIAL
Identifiers:: MONDO: MONDO:0011013; MedGen: C0342345; OMIM: 601198

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004569537	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11231970, 12469911, 31672324, 32347971, 23966241, 9395465, 18796518, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004569537

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 17, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel mutation in the calcium-sensing receptor gene in a Chinese subject with persistent hypercalcemia and hypocalciuria.

Jap TS, Wu YC, Jenq SF, Won GS.

J Clin Endocrinol Metab. 2001 Jan;86(1):13-5.

PubMed [citation]

PMID:: 11231970

Familial hypocalciuric hypercalcemia caused by an R648stop mutation in the calcium-sensing receptor gene.

Yamauchi M, Sugimoto T, Yamaguchi T, Yano S, Wang J, Bai M, Brown EM, Chihara K.

J Bone Miner Res. 2002 Dec;17(12):2174-82.

PubMed [citation]

PMID:: 12469911

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV004569537.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Arg648*) in the CASR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 431 amino acid(s) of the CASR protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 11231970, 12469911, 31672324, 32347971). ClinVar contains an entry for this variant (Variation ID: 8341). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CASR function (PMID: 23966241). This variant disrupts a region of the CASR protein in which other variant(s) (p.Trp718*) have been determined to be pathogenic (PMID: 9395465, 18796518). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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