Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000489583 | SCV000576836 | pathogenic | not provided | 2017-04-18 | criteria provided, single submitter | clinical testing | The E127A variant has been published previously in association with hypocalcaemia (Pollak et al., 1994). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). E127A 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. Functional studies have shown E127A to be a gain-of-function variant (Pollak et al., 1994; Young et al., 2015). Missense variants in the same codon (E127K/G) and in nearby residues (L123S, N124K, L125F/P, F128L, C129S/R/F/S/Y, C131S/Y/F/W) have been reported in the Human Gene Mutation Database in association with CASR-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic. |
| Invitae | RCV001060775 | SCV001225486 | pathogenic | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2023-10-20 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 127 of the CASR protein (p.Glu127Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hypocalcemia (PMID: 7874174). It has also been observed to segregate with disease in related individuals. This variant is also known as Glu128Ala. ClinVar contains an entry for this variant (Variation ID: 8315). 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: 7874174, 8702647). For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002482842 | SCV002781941 | pathogenic | Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1 | 2022-04-27 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000008815 | SCV000029025 | pathogenic | Autosomal dominant hypocalcemia 1 | 1994-11-01 | no assertion criteria provided | literature only |