Submissions for variant NM_000388.4(CASR):c.209G>A (p.Trp70Ter)

dbSNP: rs2107627458

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001873792	SCV002150189	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2022-05-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp70*) 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: 22422767). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CASR-related conditions. ClinVar contains an entry for this variant (Variation ID: 1177515). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003399331	SCV004122172	pathogenic	Familial hypocalciuric hypercalcemia	2023-10-26	criteria provided, single submitter	clinical testing	Variant summary: CASR c.209G>A (p.Trp70X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic by our laboratory (example, c.303C>A p.Cys101X). The variant was absent in 251300 control chromosomes. To our knowledge, no occurrence of c.209G>A in individuals affected with Familial Hypocalciuric Hypercalcemia or other CASR-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV001535770	SCV001749914	not provided	Neonatal severe primary hyperparathyroidism; Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1; Bartter syndrome with hypocalcemia		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12-03-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.