Submissions for variant NM_000388.4(CASR):c.2147G>A (p.Arg716His)

gnomAD frequency: 0.00001  dbSNP: rs201670662

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000477532	SCV000550990	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 716 of the CASR protein (p.Arg716His). This variant is present in population databases (rs201670662, gnomAD 0.003%). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 21414629). ClinVar contains an entry for this variant (Variation ID: 410351). 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. 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.
Illumina Laboratory Services, Illumina	RCV001145144	SCV001305786	uncertain significance	Neonatal severe primary hyperparathyroidism	2017-04-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001145145	SCV001305787	uncertain significance	Familial hypoparathyroidism	2017-04-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001145146	SCV001305788	uncertain significance	Autosomal dominant hypocalcemia 1	2017-04-28	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001147114	SCV001307892	uncertain significance	Familial hypocalciuric hypercalcemia 1	2017-04-28	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV002429523	SCV002730624	uncertain significance	Inborn genetic diseases; Nephrolithiasis/nephrocalcinosis	2022-05-02	criteria provided, single submitter	clinical testing	The p.R716H variant (also known as c.2147G>A), located in coding exon 6 of the CASR gene, results from a G to A substitution at nucleotide position 2147. The arginine at codon 716 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in an infant with mild hypercalcemia and in the unaffected mother (Koltin D et al. J. Pediatr., 2011 Aug;159:215-21.e1). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002481457	SCV002793702	uncertain significance	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2022-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226297	SCV003922648	uncertain significance	not specified	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: CASR c.2147G>A (p.Arg716His) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251258 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2147G>A has been reported in the literature in an individual affected with infantile hypercalcemia and the unaffected mother (example: Koltin_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Dominant Hypocalcemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.