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

gnomAD frequency: 0.00086  dbSNP: rs115230894

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081459	SCV000284783	benign	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000251515	SCV000306958	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000281394	SCV000440095	likely benign	Autosomal dominant hypocalcemia 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000337880	SCV000440096	likely benign	Familial hypocalciuric hypercalcemia 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000390791	SCV000440097	likely benign	Neonatal severe primary hyperparathyroidism	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000312098	SCV000440098	likely benign	Familial hypoparathyroidism	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000727289	SCV000581748	uncertain significance	not provided	2017-03-21	criteria provided, single submitter	clinical testing	The R544Q variant previously has been reported previously as a rare variant in association with familial hypocalciuric hypercalcemia (FHH) (Nissen et al., 2012). It is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R544Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties and occurs at a position that is conserved in mammals. Missense variants in nearby residues (C542R, C546S, G549R) have been reported in the Human Gene Mutation Database in association with hypocalciuric hypercalcaemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Eurofins Ntd Llc (ga)	RCV000727289	SCV000707277	uncertain significance	not provided	2017-04-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002318969	SCV001172962	likely benign	Inborn genetic diseases; Nephrolithiasis/nephrocalcinosis	2022-06-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000251515	SCV002051185	likely benign	not specified	2021-12-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000251515	SCV002070992	uncertain significance	not specified	2021-07-06	criteria provided, single submitter	clinical testing	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.
New York Genome Center	RCV001838993	SCV002099423	uncertain significance	Epilepsy, idiopathic generalized, susceptibility to, 8	2021-02-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255323	SCV002531528	likely benign	Hereditary cancer-predisposing syndrome	2020-08-21	criteria provided, single submitter	curation
Daryl Scott Lab, Baylor College of Medicine	RCV000390791	SCV002567947	uncertain significance	Neonatal severe primary hyperparathyroidism	2022-08-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000251515	SCV004024949	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727289	SCV004562246	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	The CASR c.1631G>A; p.Arg544Gln variant (rs115230894) is reported in the literature in individuals with primary hyperparathyroidism or familial hypocalciuric hypercalcemia (Bhangu 2022, Cavaco 2018, Nissen 2012). This variant is also reported in ClinVar (Variation ID: 237758). It is observed in the general population with an overall allele frequency of 0.087% (245/282890 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.337). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bhangu JS et al. Novel mutations of the calcium-sensing receptor impede differential diagnosis of primary hyperparathyroidism and familial hypocalciuric hypercalcemia. Gland Surg. 2022 Jan;11(1):12-22. PMID: 35242665. Cavaco BM et al. Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism. J Clin Endocrinol Metab. 2018 Aug 1;103(8):2879-2888. PMID: 29846619. Nissen PH et al. Identification of rare and frequent variants of the CASR gene by high-resolution melting. Clin Chim Acta. 2012 Mar 22;413(5-6):605-11. PMID: 22192860.
CeGaT Center for Human Genetics Tuebingen	RCV000727289	SCV004701249	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CASR: BP4