NM_000388.4(CASR):c.1631G>A (p.Arg544Gln) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Feb 6, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000251515.22

Allele description [Variation Report for NM_000388.4(CASR):c.1631G>A (p.Arg544Gln)]

NM_000388.4(CASR):c.1631G>A (p.Arg544Gln)

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.1631G>A (p.Arg544Gln)

HGVS:

NC_000003.12:g.122282135G>A
NG_009058.1:g.103453G>A
NM_000388.4:c.1631G>AMANE SELECT
NM_001178065.2:c.1661G>A
NP_000379.3:p.Arg544Gln
NP_001171536.2:p.Arg554Gln
NC_000003.11:g.122000982G>A
NM_000388.3:c.1631G>A
NM_001178065.1:c.1661G>A

Protein change:

R544Q

Links:

dbSNP: rs115230894

NCBI 1000 Genomes Browser:

rs115230894

Molecular consequence:

NM_000388.4:c.1631G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178065.2:c.1661G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000306958	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002051185	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Dec 17, 2021)	germline	clinical testing	Citation Link,
SCV002070992	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004024949	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 6, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV000306958.1

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

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002051185.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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

From Genetic Services Laboratory, University of Chicago, SCV002070992.1

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

Description

DNA sequence analysis of the CASR gene demonstrated a sequence change, c.1631G>A, in exon 6 that results in an amino acid change, p.Arg544Gln. This sequence change has been described in the gnomAD database with a frequency of 0.6% in the Ashkenazi Jewish subpopulation (dbSNP rs115230894). The p.Arg544Gln change affects a moderately conserved amino acid residue located in a domain of the CASR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg544Gln substitution. This variant has been reported in the homozygous state in an individual with hypocalcemic hypoparathyroidism (PMID: 29846619). The authors suggest this variant may be pathogenic in the homozygous state but is unlikely to contribute to disease in the heterozygous state. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg544Gln change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV004024949.2

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

#	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: Apr 15, 2024

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