NM_000388.4(CASR):c.2269G>A (p.Glu757Lys) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 11, 2020
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:: RCV001315659.7

Allele description [Variation Report for NM_000388.4(CASR):c.2269G>A (p.Glu757Lys)]

NM_000388.4(CASR):c.2269G>A (p.Glu757Lys)

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.2269G>A (p.Glu757Lys)

HGVS:

NC_000003.12:g.122284223G>A
NG_009058.2:g.105556G>A
NM_000388.4:c.2269G>AMANE SELECT
NM_001178065.2:c.2299G>A
NP_000379.3:p.Glu757Lys
NP_001171536.2:p.Glu767Lys
NC_000003.11:g.122003070G>A
NG_009058.1:g.105541G>A

Protein change:

E757K

Links:

dbSNP: rs2074935149

NCBI 1000 Genomes Browser:

rs2074935149

Molecular consequence:

NM_000388.4:c.2269G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178065.2:c.2299G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001506246	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 11, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30306783, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001506246

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 11, 2020)

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

A novel CASR mutation (p.Glu757Lys) causing autosomal dominant hypocalcaemia type 1

Kwan B, Champion B, Boyages S, Munns CF, Clifton-Bligh R, Luxford C, Crawford B.

Endocrinol Diabetes Metab Case Rep. 2018 Sep 25;2018. doi:pii: EDM180107. 10.1530/EDM-18-0107.

PubMed [citation]

PMID:: 30306783
PMCID:: PMC6169543

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, SCV001506246.4

#	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 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with basal ganglia calcification and/or hypocalcemia and (PMID: 30306783, Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 757 of the CASR protein (p.Glu757Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.

#	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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