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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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV004585870Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Nov 30, 2022)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024