Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002228022 | SCV000831123 | likely pathogenic | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2023-09-06 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 138 of the CASR protein (p.Thr138Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant CASR-related conditions (PMID: 1302026, 7726161, 11889203, 22422767, 26963950, 32347971). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr139Met. ClinVar contains an entry for this variant (Variation ID: 8332). 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: 8702647, 21239511). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Fulgent Genetics, |
RCV002476947 | SCV002796843 | likely pathogenic | Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1 | 2021-10-19 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004554589 | SCV004119769 | likely pathogenic | CASR-related disorder | 2022-11-21 | criteria provided, single submitter | clinical testing | The CASR c.413C>T variant is predicted to result in the amino acid substitution p.Thr138Met. This variant has been reported to segregate with disease in two families with hypocalciuric hypercalcemia (Chou et al 1995. PubMed ID: 7726161; Mouly et al 2020. PubMed ID: 32347971). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. |
| Mayo Clinic Laboratories, |
RCV003480025 | SCV004226752 | pathogenic | not provided | 2023-03-07 | criteria provided, single submitter | clinical testing | PP1_strong, PP2, PM1_supporting, PM2_supporting, PS3, PS4_moderate |
| Ambry Genetics | RCV004018594 | SCV005035424 | pathogenic | Nephrolithiasis/nephrocalcinosis | 2023-09-16 | criteria provided, single submitter | clinical testing | The p.T138M pathogenic mutation (also known as c.413C>T), located in coding exon 2 of the CASR gene, results from a C to T substitution at nucleotide position 413. The threonine at codon 138 is replaced by methionine, an amino acid with similar properties. This alteration was identified in multiple individuals with familial hypocalciuric hypercalcemia (FHH) (D'Souza-Li L et al. J Clin Endocrinol Metab, 2002 Mar;87:1309-18; Alam S et al. Indian J Endocrinol Metab, 2021 Jan;25:462-465; Bernardor J et al. Front Pediatr, 2022 Aug;10:926986; Ambry internal data) and segregated with disease in one large family (Chou YH et al. Am J Hum Genet, 1995 May;56:1075-9). This alteration was also identified in the homozygous state in an individual diagnosed with neonatal severe hyperparathyroidism (NSHPT) (Bernardor J et al. Front Pediatr, 2022 Aug;10:926986). In one functional study, this alteration showed reduced CASR function when exposed to extracellular calcium (Bai M et al. J Biol Chem, 1996 Aug;271:19537-45). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| OMIM | RCV000008834 | SCV000029044 | pathogenic | Familial hypocalciuric hypercalcemia 1 | 1995-05-01 | no assertion criteria provided | literature only |