NM_000388.4(CASR):c.2329A>C (p.Ile777Leu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 15, 2019
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:: RCV001205834.9

Allele description [Variation Report for NM_000388.4(CASR):c.2329A>C (p.Ile777Leu)]

NM_000388.4(CASR):c.2329A>C (p.Ile777Leu)

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.2329A>C (p.Ile777Leu)

HGVS:

NC_000003.12:g.122284283A>C
NG_009058.2:g.105616A>C
NM_000388.4:c.2329A>CMANE SELECT
NM_001178065.2:c.2359A>C
NP_000379.3:p.Ile777Leu
NP_001171536.2:p.Ile787Leu
NC_000003.11:g.122003130A>C
NG_009058.1:g.105601A>C
NM_000388.3:c.2329A>C

Protein change:

I777L

Links:

dbSNP: rs2074936383

NCBI 1000 Genomes Browser:

rs2074936383

Molecular consequence:

NM_000388.4:c.2329A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001178065.2:c.2359A>C - 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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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001377111	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 15, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27666534, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001377111

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 15, 2019)

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

Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype.

Glaudo M, Letz S, Quinkler M, Bogner U, Elbelt U, Strasburger CJ, Schnabel D, Lankes E, Scheel S, Feldkamp J, Haag C, Schulze E, Frank-Raue K, Raue F, Mayr B, Schöfl C.

Eur J Endocrinol. 2016 Nov;175(5):421-31. doi: 10.1530/EJE-16-0223.

PubMed [citation]

PMID:: 27666534

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, SCV001377111.5

#	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 isoleucine with leucine at codon 777 of the CASR protein (p.Ile777Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant has been observed in an individual with clinical features of familial hypocalciuric hypercalcemia (PMID: 27666534). This variant has been reported to have conflicting or insufficient data to determine the effect on CASR protein function (PMID:¬†27666534). 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. This variant is not present in population databases (ExAC no frequency).

#	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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