NM_000388.4(CASR):c.680G>T (p.Arg227Leu) AND Neonatal severe primary hyperparathyroidism

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 3, 2024
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:: RCV000008818.8

Allele description [Variation Report for NM_000388.4(CASR):c.680G>T (p.Arg227Leu)]

NM_000388.4(CASR):c.680G>T (p.Arg227Leu)

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.680G>T (p.Arg227Leu)

HGVS:

NC_000003.12:g.122261715G>T
NG_009058.1:g.83033G>T
NM_000388.4:c.680G>TMANE SELECT
NM_001178065.1:c.680G>T
NM_001178065.2:c.680G>T
NP_000379.3:p.Arg227Leu
NP_001171536.2:p.Arg227Leu
NC_000003.11:g.121980562G>T
NM_000388.4:c.680G>T

Protein change:

R227L; ARG227LEU

Links:

OMIM: 601199.0006; dbSNP: rs28936684

NCBI 1000 Genomes Browser:

rs28936684

Molecular consequence:

NM_000388.4:c.680G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178065.2:c.680G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neonatal severe primary hyperparathyroidism
Synonyms:: Neonatal severe hyperparathyroidism
Identifiers:: MONDO: MONDO:0009397; MedGen: C1832615; Orphanet: 417; OMIM: 239200

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DGKI [Sphaerodactylus townsendi]
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Gene ID:125434498

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000029028	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2005)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8675635, 15572418
SCV005203731	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 3, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8675635, 15572418, 32306059 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000029028

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2005)

germline

literature only

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

SCV005203731

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 3, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.

Pearce SH, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, Heath DA, Hughes IA, Paterson CR, Whyte MP, et al.

J Clin Invest. 1995 Dec;96(6):2683-92.

PubMed [citation]

PMID:: 8675635
PMCID:: PMC185975

Functional characterization of calcium-sensing receptor codon 227 mutations presenting as either familial (benign) hypocalciuric hypercalcemia or neonatal hyperparathyroidism.

Wystrychowski A, Pidasheva S, Canaff L, Chudek J, Kokot F, Wiecek A, Hendy GN.

J Clin Endocrinol Metab. 2005 Feb;90(2):864-70. Epub 2004 Nov 30.

PubMed [citation]

PMID:: 15572418

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000029028.5

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

Description

In a sporadic case of neonatal hyperparathyroidism (NSHPT; 239200), Pearce et al. (1995) found a heterozygous CGA-to-CTA transversion in codon 227 of exon 4, resulting in an amino acid substitution of leucine for arginine (R227L).

Wystrychowski et al. (2005) performed a functional analysis comparing the R227L and R227Q mutations (see 601199.0049).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005203731.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: CASR c.680G>T (p.Arg227Leu) results in a non-conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250970 control chromosomes (gnomAD). c.680G>T has been reported in the literature in an individual affected with Neonatal Hyperparathyroidism as a de novo occurrence (Pearce_1995), as well as in an individual affected with Familial Hypocalciuric Hypercalcemia (Veldeman_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in impaired MAPK response to extracellular calcium levels (Wystrychowski_2005). The following publications have been ascertained in the context of this evaluation (PMID: 8675635, 15572418, 32306059). ClinVar contains an entry for this variant (Variation ID: 8317). Based on the evidence outlined above, the variant was classified as 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: Oct 13, 2024

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