Submissions for variant NM_000388.4(CASR):c.2039G>A (p.Arg680His)

gnomAD frequency: 0.00001  dbSNP: rs773146939

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231951	SCV000284788	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2024-11-18	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 680 of the CASR protein (p.Arg680His). This variant is present in population databases (rs773146939, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of hypocalciuric hypercalcemia, hyperparathyroidism and/or neonatal severe hyperparathyroidism (PMID: 19179454, 26646938, 26963950, 27666534, 32347971; internal data). 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: 237763). 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: 22798347, 23372019). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000991741	SCV001143434	likely pathogenic	not provided	2019-04-11	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Damaging to protein function(s) relevant to disease mechanism.
Fulgent Genetics, Fulgent Genetics	RCV002494624	SCV002794697	pathogenic	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2022-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235152	SCV003934483	pathogenic	Familial hypocalciuric hypercalcemia	2023-05-12	criteria provided, single submitter	clinical testing	Variant summary: CASR c.2039G>A (p.Arg680His) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251122 control chromosomes. c.2039G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (FHH) and in the homozygous state in one individual with Neonatal Severe Hyperparathyroidism whose parents were both FHH-affected (e.g. Cole_2009, Vargas-Poussou_2016, Mouly_2020, Kurian_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence has shown that although the variant does not significantly alter the EC50 and results in only a mild reduction in the maximal Ca2+ response when studied in vitro, it results in a reduction in cell surface expression to 7% of normal, suggesting the variant has a damaging effect (e.g. Glaudo_2016, Leach_2012). Additionally, a variant affecting the same amino acid, c.2038C>T (p.Arg680Cys), has been classified as pathogenic, suggesting the Arg680 residue is important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 19179454, 11013439, 34993031, 22798347, 32347971, 26963950, 27666534). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=1)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000991741	SCV004226758	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	PP2, PP3, PM1, PM5, PS3