NM_000388.4(CASR):c.1393C>T (p.Arg465Trp) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 4, 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:: RCV000468370.14

Allele description [Variation Report for NM_000388.4(CASR):c.1393C>T (p.Arg465Trp)]

NM_000388.4(CASR):c.1393C>T (p.Arg465Trp)

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.1393C>T (p.Arg465Trp)

Other names:

p.Arg465Trp

HGVS:

NC_000003.12:g.122275827C>T
NG_009058.1:g.97145C>T
NM_000388.4:c.1393C>TMANE SELECT
NM_001178065.2:c.1393C>T
NP_000379.3:p.Arg465Trp
NP_001171536.2:p.Arg465Trp
NC_000003.11:g.121994674C>T
NM_000388.3:c.1393C>T

Protein change:

R465W

Links:

dbSNP: rs751217000

NCBI 1000 Genomes Browser:

rs751217000

Molecular consequence:

NM_000388.4:c.1393C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178065.2:c.1393C>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000550986	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 4, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 29026550, 31672324, 32347971, 20164288, 16598859, 26646938, 26963950, 28176280, 30407919, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000550986

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 4, 2023)

germline

clinical testing

PubMed (10)
[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

Making (mis) sense of asymptomatic marked hypercalcemia in pregnancy.

Maltese G, Izatt L, McGowan BM, Hafeez K, Hubbard JG, Carroll PV.

Clin Case Rep. 2017 Oct;5(10):1587-1590. doi: 10.1002/ccr3.1074.

PubMed [citation]

PMID:: 29026550
PMCID:: PMC5628236

High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults.

Hureaux M, Ashton E, Dahan K, Houillier P, Blanchard A, Cormier C, Koumakis E, Iancu D, Belge H, Hilbert P, Rotthier A, Del Favero J, Schaefer F, Kleta R, Bockenhauer D, Jeunemaitre X, Devuyst O, Walsh SB, Vargas-Poussou R.

Kidney Int. 2019 Dec;96(6):1408-1416. doi: 10.1016/j.kint.2019.08.027. Epub 2019 Sep 16.

PubMed [citation]

PMID:: 31672324

See all PubMed Citations (10)

Details of each submission

From Invitae, SCV000550986.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 465 of the CASR protein (p.Arg465Trp). This variant is present in population databases (rs751217000, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of familial hypocalciuric hypercalcemia (FHH) (PMID: 20164288, 29026550, 31672324, 32347971; Invitae). ClinVar contains an entry for this variant (Variation ID: 410348). 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: 20164288). This variant disrupts the p.Arg465 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16598859, 26646938, 26963950, 28176280, 30407919; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: May 7, 2024

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