Submissions for variant NM_000388.4(CASR):c.2254C>T (p.Arg752Cys)

dbSNP: rs193922434

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029442	SCV000052092	uncertain significance	not specified	2019-01-22	criteria provided, single submitter	clinical testing	Variant summary: The variant, CASR c.2254C>T (p.Arg752Cys) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245378 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant c.2254C>T has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (Hannan_2012). However, this report does not provide unequivocal conclusions about association of the variant with Familial Hypocalciuric Hypercalcemia (FHH). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228056	SCV000761034	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-08-24	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 35790). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 22422767). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 752 of the CASR protein (p.Arg752Cys).
GeneDx	RCV001753429	SCV001986152	uncertain significance	not provided	2019-07-31	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22422767)