NM_000388.4(CASR):c.2243C>G (p.Pro748Arg) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 9, 2019
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:: RCV001205771.4

Allele description [Variation Report for NM_000388.4(CASR):c.2243C>G (p.Pro748Arg)]

NM_000388.4(CASR):c.2243C>G (p.Pro748Arg)

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.2243C>G (p.Pro748Arg)

HGVS:

NC_000003.12:g.122284197C>G
NG_009058.2:g.105530C>G
NM_000388.4:c.2243C>GMANE SELECT
NM_001178065.2:c.2273C>G
NP_000379.3:p.Pro748Arg
NP_001171536.2:p.Pro758Arg
NC_000003.11:g.122003044C>G
NG_009058.1:g.105515C>G
NM_000388.2:c.2243C>G
NM_000388.3:c.2243C>G

Protein change:

P748R

Links:

dbSNP: rs193922433

NCBI 1000 Genomes Browser:

rs193922433

Molecular consequence:

NM_000388.4:c.2243C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001178065.2:c.2273C>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001377045	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 9, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22798347, 8636323, 22232026, 19389809, 23372019, 26963950, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001377045

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 9, 2019)

germline

clinical testing

PubMed (7)
[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

Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor.

Leach K, Wen A, Davey AE, Sexton PM, Conigrave AD, Christopoulos A.

Endocrinology. 2012 Sep;153(9):4304-16. doi: 10.1210/en.2012-1449. Epub 2012 Jul 13.

PubMed [citation]

PMID:: 22798347

Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains.

Heath H 3rd, Odelberg S, Jackson CE, Teh BT, Hayward N, Larsson C, Buist NR, Krapcho KJ, Hung BC, Capuano IV, Garrett JE, Leppert MF.

J Clin Endocrinol Metab. 1996 Apr;81(4):1312-7.

PubMed [citation]

PMID:: 8636323

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001377045.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces proline with arginine at codon 748 of the CASR protein (p.Pro748Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several families affected with familial hypocalciuric hypercalcemia and to segregate with disease in a family (PMID: 8636323, 26963950). This variant has also been observed in an individual affected with familial hypocalciuric hypercalcemia and primary hyperparathyroidism (PMID: 22232026). This variant has been reported to affect CASR protein function (PMID: 19389809, 22798347, 23372019). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 29, 2024

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