Submissions for variant NM_000388.4(CASR):c.680G>A (p.Arg227Gln)

dbSNP: rs28936684

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524505	SCV000550964	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2025-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the CASR protein (p.Arg227Gln). This variant is present in population databases (rs28936684, gnomAD 0.0009%). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (FHH) (PMID: 1302026, 7726161, 15572418, 22422767, 26963950). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this CASR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 606,512 individuals referred to our laboratory for CASR testing. ClinVar contains an entry for this variant (Variation ID: 8331). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 19389809, 19759318, 23077345, 27666534). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000516668	SCV000612677	pathogenic	not provided	2017-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265551	SCV002548004	pathogenic	Familial hypocalciuric hypercalcemia	2022-05-24	criteria provided, single submitter	clinical testing	Variant summary: CASR c.680G>A (p.Arg227Gln) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251070 control chromosomes (gnomAD and publication data). c.680G>A has been reported in the literature in multiple individuals affected with Familial Hypocalciuric Hypercalcemia (Chou_1992, Wystrychowski_2005, Glaudo_2016). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and results in reducing ability to induce ERK1/2 phosphorylation (Wystrychowski_2005, White_2009, Glaudo_2016). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496308	SCV002795807	pathogenic	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2021-12-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554588	SCV004106970	pathogenic	CASR-related disorder	2023-08-02	criteria provided, single submitter	clinical testing	The CASR c.680G>A variant is predicted to result in the amino acid substitution p.Arg227Gln. This variant has been reported in multiple individuals with familial hypocalciuric hypocalcemia (FHH) (Chou et al. 1995. PubMed ID: 7726161; Wystrychowski et al. 2005. PubMed ID: 15572418; Hannan et al. 2012. PubMed ID: 22422767; Vargas-Poussou et al. 2016. PubMed ID: 26963950). Additionally, several in vitro experimental studies have demonstrated that CASR protein carrying the p.Arg227Gln variant has impaired sensitivity to elevated extracellular calcium levels relative to wild type (Wystrychowski et al. 2005. PubMed ID: 15572418; White et al. 2009. PubMed ID: 19389809; Grant et al. 2012. PubMed ID: 23077345; Glaudo et al. 2016. PubMed ID: 27666534). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-121980562-G-A). Alternate nucleotide changes affecting the same amino acid (p.Arg227Leu, p.Arg227Gly) have also been reported as pathogenic in individuals with CASR-associated disease (Pearce et al. 1995. PubMed ID: 8675635; Glaudo et al. 2016. PubMed ID: 27666534). Taken together, the p.Arg227Gln variant is interpreted as pathogenic.
Ambry Genetics	RCV004018593	SCV005034814	likely pathogenic	Nephrolithiasis/nephrocalcinosis	2023-08-08	criteria provided, single submitter	clinical testing	The p.R227Q variant (also known as c.680G>A), located in coding exon 3 of the CASR gene, results from a G to A substitution at nucleotide position 680. The arginine at codon 227 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in two unrelated families with familial hypocalciuric hypercalcemia and segregated with affected individuals in these families (Chou YH et al. Am J Hum Genet, 1995 May;56:1075-9; Wystrychowski A et al. J Clin Endocrinol Metab, 2005 Feb;90:864-70). In vitro functional studies showed that cells expressing R227Q have decreased sensitivity to extracellular calcium concentrations (Wystrychowski A et al. J Clin Endocrinol Metab, 2005 Feb;90:864-70; Lu JY et al. J Pharmacol Exp Ther, 2009 Dec;331:775-86; Grant MP et al. Mol Endocrinol, 2012 Dec;26:2081-91; Glaudo M et al. Eur J Endocrinol, 2016 Nov;175:421-31). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
OMIM	RCV000008833	SCV000029043	pathogenic	Familial hypocalciuric hypercalcemia 1	1995-05-01	no assertion criteria provided	literature only