NM_000388.4(CASR):c.2657G>C (p.Arg886Pro) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 11, 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:: RCV000694836.8

Allele description [Variation Report for NM_000388.4(CASR):c.2657G>C (p.Arg886Pro)]

NM_000388.4(CASR):c.2657G>C (p.Arg886Pro)

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.2657G>C (p.Arg886Pro)

HGVS:

NC_000003.12:g.122284611G>C
NG_009058.1:g.105929G>C
NM_000388.4:c.2657G>CMANE SELECT
NM_001178065.2:c.2687G>C
NP_000379.3:p.Arg886Pro
NP_001171536.2:p.Arg896Pro
NC_000003.11:g.122003458G>C
NM_000388.3:c.2657G>C

Protein change:

R886P; ARG886PRO

Links:

LOVD 3: CASR_00066; OMIM: 601199.0054; dbSNP: rs1057520791

NCBI 1000 Genomes Browser:

rs1057520791

Molecular consequence:

NM_000388.4:c.2657G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001178065.2:c.2687G>C - 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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Mus musculus paraoxonase-3 (Pon3) mRNA, complete cds
Mus musculus paraoxonase-3 (Pon3) mRNA, complete cds
gi|1333639|gb|L76193.1|MUSPON3R

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000823298	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 11, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11807402, 20798521, 17698911, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000823298

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 11, 2023)

germline

clinical testing

PubMed (4)
[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

Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds.

Simonds WF, James-Newton LA, Agarwal SK, Yang B, Skarulis MC, Hendy GN, Marx SJ.

Medicine (Baltimore). 2002 Jan;81(1):1-26. Review. No abstract available.

PubMed [citation]

PMID:: 11807402

Calcium sensing receptor mutations implicated in pancreatitis and idiopathic epilepsy syndrome disrupt an arginine-rich retention motif.

Stepanchick A, McKenna J, McGovern O, Huang Y, Breitwieser GE.

Cell Physiol Biochem. 2010;26(3):363-74. doi: 10.1159/000320560. Epub 2010 Aug 24.

PubMed [citation]

PMID:: 20798521
PMCID:: PMC3709174

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000823298.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 886 of the CASR protein (p.Arg886Pro). 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: 11807402). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 379932). 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: 20798521). This variant disrupts the p.Arg886 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17698911). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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 29, 2024

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