Submissions for variant NM_000388.4(CASR):c.1378-1G>C

dbSNP: rs2074810403

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001825078	SCV002074234	likely pathogenic	Familial hypocalciuric hypercalcemia	2022-01-13	criteria provided, single submitter	clinical testing	Variant summary: CASR c.1378-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site with two of them also predicting the variant creates a cryptic exonic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251008 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1378-1G>C in individuals affected with Familial Hypocalciuric Hypercalcemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002542765	SCV003231536	likely pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2022-09-03	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1339690). Disruption of this splice site has been observed in individual(s) with neonatal severe hyperparathyroidism (PMID: 29354167). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the CASR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CASR are known to be pathogenic (PMID: 11807402, 14985373, 22422767).