NM_000388.4(CASR):c.2203C>A (p.Gln735Lys) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 30, 2022
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:: RCV003766911.2

Allele description [Variation Report for NM_000388.4(CASR):c.2203C>A (p.Gln735Lys)]

NM_000388.4(CASR):c.2203C>A (p.Gln735Lys)

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.2203C>A (p.Gln735Lys)

HGVS:

NC_000003.12:g.122284157C>A
NG_009058.1:g.105475C>A
NM_000388.4:c.2203C>AMANE SELECT
NM_001178065.2:c.2233C>A
NP_000379.3:p.Gln735Lys
NP_001171536.2:p.Gln745Lys
NC_000003.11:g.122003004C>A
NM_000388.2:c.2203C>A
p.GLN735LYS

Protein change:

Q735K

Links:

dbSNP: rs1553769052

NCBI 1000 Genomes Browser:

rs1553769052

Molecular consequence:

NM_000388.4:c.2203C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178065.2:c.2233C>A - 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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C1844662[conceptid] (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004585870	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 30, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32347971, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004585870

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 30, 2022)

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

Clinical characteristics of familial hypocalciuric hypercalcaemia type 1: A multicentre study of 77 adult patients.

Mouly C, Vargas-Poussou R, Lienhardt A, Silve C, Hureaux M, Magdelaine C, Buffet A, Grunenwald S, Kuhn JM, Brue T, Reznik Y, Tabarin A, Martin-Coignard D, Haymann JP, Tack I, Bennet A, Caron P, Linglart A, Vezzosi D; Reference Centre for Rare Diseases of Calcium, Phosphate Metabolism..

Clin Endocrinol (Oxf). 2020 Sep;93(3):248-260. doi: 10.1111/cen.14211. Epub 2020 May 14.

PubMed [citation]

PMID:: 32347971

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, SCV004585870.1

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

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 446991). This missense change has been observed in individual(s) with hypocalciuric hypercalcemia (PMID: 32347971; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 735 of the CASR protein (p.Gln735Lys).

#	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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