NM_000388.4(CASR):c.2299G>A (p.Glu767Lys) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 8, 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:: RCV001233441.8

Allele description [Variation Report for NM_000388.4(CASR):c.2299G>A (p.Glu767Lys)]

NM_000388.4(CASR):c.2299G>A (p.Glu767Lys)

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.2299G>A (p.Glu767Lys)

HGVS:

NC_000003.12:g.122284253G>A
NG_009058.2:g.105586G>A
NM_000388.4:c.2299G>AMANE SELECT
NM_001178065.2:c.2329G>A
NP_000379.3:p.Glu767Lys
NP_001171536.2:p.Glu777Lys
NC_000003.11:g.122003100G>A
NG_009058.1:g.105571G>A
NM_000388.3:c.2299G>A

Protein change:

E767K

Links:

dbSNP: rs2074935748

NCBI 1000 Genomes Browser:

rs2074935748

Molecular consequence:

NM_000388.4:c.2299G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178065.2:c.2329G>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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ENPP3 [Taeniopygia guttata]
ENPP3 [Taeniopygia guttata]
Gene ID:100219928

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001406035	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15551332, 22798347, 23372019, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001406035

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 8, 2023)

germline

clinical testing

PubMed (4)
[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 mutation (E767K) in the second extracellular loop of the calcium sensing receptor in a family with autosomal dominant hypocalcemia.

Uçkun-Kitapçi A, Underwood LE, Zhang J, Moats-Staats B.

Am J Med Genet A. 2005 Jan 15;132A(2):125-9.

PubMed [citation]

PMID:: 15551332

Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor.

Leach K, Wen A, Davey AE, Sexton PM, Conigrave AD, Christopoulos A.

Endocrinology. 2012 Sep;153(9):4304-16. doi: 10.1210/en.2012-1449. Epub 2012 Jul 13.

PubMed [citation]

PMID:: 22798347

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001406035.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

ClinVar contains an entry for this variant (Variation ID: 959995). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 767 of the CASR protein (p.Glu767Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypocalcemia and/or hypoparathyroidism (PMID: 15551332; Invitae). It has also been observed to segregate with disease in related individuals. 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: 22798347, 23372019). 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: Sep 29, 2024

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