Submissions for variant NM_000388.4(CASR):c.1183T>C (p.Cys395Arg)

dbSNP: rs1057517712

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413522	SCV000490455	likely pathogenic	not provided	2016-09-12	criteria provided, single submitter	clinical testing	The C395R variant in the CASR gene has been reported previously in association with familial hypocalciuric hypercalcemia (Vigouroux et al., 2000; Forde et al., 2014). In vitro functional studies indicate that this variant results in defective tracking to its functional location in the cell's plasma membrane (White et al., 2009). The C395R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C395R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. The C395R variant is a strong candidate for a pathogenic variant; however the possibility it may be a rare benign variant cannot be excluded.
Invitae	RCV002523905	SCV003525273	likely pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 395 of the CASR protein (p.Cys395Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercalcemia (PMID: 10971459, 25320261). ClinVar contains an entry for this variant (Variation ID: 372316). 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, 23077345, 32386559). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.