Submissions for variant NM_000388.4(CASR):c.893C>T (p.Ala298Val)

dbSNP: rs1064797049

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486912	SCV000574403	uncertain significance	not provided	2017-03-27	criteria provided, single submitter	clinical testing	The A298V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). A298V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV002230961	SCV000825070	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 298 of the CASR protein (p.Ala298Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant hypocalciuric hypercalcemia (PMID: 32347971, 34714514). ClinVar contains an entry for this variant (Variation ID: 424581). 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.
Athena Diagnostics Inc	RCV000486912	SCV002771685	uncertain significance	not provided	2021-10-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235243	SCV003934484	uncertain significance	not specified	2023-05-23	criteria provided, single submitter	clinical testing	Variant summary: CASR c.893C>T (p.Ala298Val) results in a non-conservative amino acid change located in the Receptor, ligand binding region domain (IPR001828) 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 251232 control chromosomes. c.893C>T has been reported in the literature in individuals affected with features of Familial Hypocalciuric Hypercalcemia (example, Mouly_2020, Lasbleiz_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34714514, 32347971). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.