Submissions for variant NM_000388.4(CASR):c.679C>T (p.Arg227Ter)

dbSNP: rs1085307984

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000639467	SCV000761042	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg227*) in the CASR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CASR are known to be pathogenic (PMID: 11807402, 14985373, 22422767). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia (PMID: 20972686, 26963950, 27666534). ClinVar contains an entry for this variant (Variation ID: 532618). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657571	SCV000779308	pathogenic	not provided	2018-05-06	criteria provided, single submitter	clinical testing	The R227X nonsense variant in the CASR gene has been reported previously in association with familial hypocalciuric hypercalcemia, as well as with neonatal severe primary hyperparathyroidism when observed in the homozygous state (Vargas-Poussou et al., 2016; Al-Khalaf et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic.
Athena Diagnostics Inc	RCV000657571	SCV001143444	pathogenic	not provided	2018-10-09	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. Damaging to protein function(s) relevant to disease mechanism.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000657571	SCV001449731	likely pathogenic	not provided	2018-12-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002499075	SCV002811681	pathogenic	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2022-01-11	criteria provided, single submitter	clinical testing