Submissions for variant NM_000388.4(CASR):c.380A>G (p.Glu127Gly)

dbSNP: rs121909260

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029450	SCV000052100	likely pathogenic	Familial hypocalciuric hypercalcemia	2023-12-22	criteria provided, single submitter	clinical testing	Variant summary: CASR c.380A>G (p.Glu127Gly) results in a non-conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251394 control chromosomes. c.380A>G has been reported in the literature in an individual affected with Hypocalciuric Hypercalcemia (Hannan_2012). Additionally, two other amino acid changes (p.Glu127Ala and p.Glu127Lys) have been classified as pathogenic/likely pathogenic in ClinVar, supporting the function importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22422767). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV000429931	SCV000521153	likely pathogenic	not provided	2018-05-23	criteria provided, single submitter	clinical testing	The E127G variant in the CASR gene has been reported previously in an individual with autosomal dominant hypocalcaemic hypercalciuria; however, familial segregation information, in vitro functional studies, and additional clinical information were not included (Hannan et al., 2012). The E127G 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 E127G 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same residue (E127A, E127K) and in nearby residues have been reported in the Human Gene Mutation Database in association with CASR-related disorders (Pollak et al., 1994; Lienhardt et al., 2001; Stenson et al., 2014), supporting the functional importance of this region of the protein. The E127G variant is a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded.