Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001233279 | SCV001405866 | pathogenic | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2023-11-28 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 218 of the CASR protein (p.Tyr218Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypocalciuric hypercalcemia (FHH) (PMID: 12580936, 25104082, 26963950, 32347971; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 959855). 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: 12580936, 19759318). For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002497795 | SCV002810058 | likely pathogenic | Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1 | 2022-02-04 | criteria provided, single submitter | clinical testing | |
| Athena Diagnostics | RCV003482350 | SCV004229522 | pathogenic | not provided | 2023-07-26 | criteria provided, single submitter | clinical testing | This variant has been identified in multiple unrelated individuals with clinical features of familial hypocalciuric hypercalcemia and segregates with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 19759318) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003486972 | SCV004241363 | pathogenic | Familial hypocalciuric hypercalcemia | 2023-12-20 | criteria provided, single submitter | clinical testing | Variant summary: CASR c.653A>G (p.Tyr218Cys) results in a non-conservative amino acid change located in the receptor, ligand binding region (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 250844 control chromosomes (gnomAD). c.653A>G has been reported in the literature in multiple individuals affected with Familial Hypocalciuric Hypercalcemia and has been found to segregate in affected members of at least one family (e.g. Cetani_2003, Stratta_2014, Mouly_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro (e.g. Cetani_2003). The most pronounced variant effect results in 10%-<30% activity compared to the WT protein. The following publications have been ascertained in the context of this evaluation (PMID: 12580936, 32347971, 25104082). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |