NM_000388.4(CASR):c.40A>G (p.Thr14Ala) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 12, 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:: RCV000524604.10

Allele description [Variation Report for NM_000388.4(CASR):c.40A>G (p.Thr14Ala)]

NM_000388.4(CASR):c.40A>G (p.Thr14Ala)

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.40A>G (p.Thr14Ala)

HGVS:

NC_000003.12:g.122254229A>G
NG_009058.1:g.75547A>G
NM_000388.4:c.40A>GMANE SELECT
NM_001178065.2:c.40A>G
NP_000379.3:p.Thr14Ala
NP_001171536.2:p.Thr14Ala
NC_000003.11:g.121973076A>G
NM_000388.3:c.40A>G

Protein change:

T14A

Links:

dbSNP: rs199515839

NCBI 1000 Genomes Browser:

rs199515839

Molecular consequence:

NM_000388.4:c.40A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001178065.2:c.40A>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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000638073	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15879434, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000638073

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 12, 2023)

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

Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia.

Pidasheva S, Canaff L, Simonds WF, Marx SJ, Hendy GN.

Hum Mol Genet. 2005 Jun 15;14(12):1679-90. Epub 2005 May 6.

PubMed [citation]

PMID:: 15879434

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, SCV000638073.9

#	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 threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 14 of the CASR protein (p.Thr14Ala). This variant is present in population databases (rs199515839, gnomAD 0.004%). This missense change has been observed in individual(s) with primary hyperparathyroidism (PMID: 15879434). ClinVar contains an entry for this variant (Variation ID: 463950). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect CASR function (PMID: 15879434). 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

ClinVar

Relating variation to medicine