NM_000388.4(CASR):c.2243C>T (p.Pro748Leu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 27, 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:: RCV000532551.5

Allele description [Variation Report for NM_000388.4(CASR):c.2243C>T (p.Pro748Leu)]

NM_000388.4(CASR):c.2243C>T (p.Pro748Leu)

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>T (p.Pro748Leu)

HGVS:

NC_000003.12:g.122284197C>T
NG_009058.1:g.105515C>T
NM_000388.4:c.2243C>TMANE SELECT
NM_001178065.2:c.2273C>T
NP_000379.3:p.Pro748Leu
NP_001171536.2:p.Pro758Leu
NC_000003.11:g.122003044C>T
NM_000388.3:c.2243C>T

Protein change:

P748L

Links:

dbSNP: rs193922433

NCBI 1000 Genomes Browser:

rs193922433

Molecular consequence:

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

Recent activity

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PREDICTED: Homo sapiens uncharacterized lncRNA (LOC105372004), transcript varian...
PREDICTED: Homo sapiens uncharacterized lncRNA (LOC105372004), transcript variant X5, ncRNA
gi|1034605211|ref|XR_935175.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000638042	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 27, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22422767, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000638042

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 27, 2019)

germline

clinical testing

PubMed (2)
[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 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites.

Hannan FM, Nesbit MA, Zhang C, Cranston T, Curley AJ, Harding B, Fratter C, Rust N, Christie PT, Turner JJ, Lemos MC, Bowl MR, Bouillon R, Brain C, Bridges N, Burren C, Connell JM, Jung H, Marks E, McCredie D, Mughal Z, Rodda C, et al.

Hum Mol Genet. 2012 Jun 15;21(12):2768-78. doi: 10.1093/hmg/dds105. Epub 2012 Mar 14.

PubMed [citation]

PMID:: 22422767

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000638042.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces proline with leucine at codon 748 of the CASR protein (p.Pro748Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) affected with familial hypocalciuric hypercalcemia (PMID: 22422767). ClinVar contains an entry for this variant (Variation ID: 463923). 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, but these predictions have not been confirmed by published functional studies. 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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