Submissions for variant NM_000388.4(CASR):c.2449G>A (p.Val817Ile)

dbSNP: rs1057518933

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415394	SCV000492958	likely pathogenic	Parathyroid gland adenoma; Hypercalcemia; Hypertrophic cardiomyopathy; Hypocalciuria	2015-01-05	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000991745	SCV001143438	likely pathogenic	not provided	2019-03-04	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/283120 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism.
Invitae	RCV001379697	SCV001577543	likely pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2021-09-19	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. Experimental studies have shown that this missense change affects CASR function (PMID: 8878438, 17284438, 22798347, 23372019). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 374153). This missense change has been observed in individuals with familial hypocalciuric hypercalcemia (FHH) (PMID: 8675635). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 817 of the CASR protein (p.Val817Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine.
GeneDx	RCV000991745	SCV001780288	likely pathogenic	not provided	2021-09-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate V817I showed reduced cell surface expression compared to wild type, as well as reduced Ca2+ potency in intracellular Ca2+ mobilization and reduced ERK1/2 phosphorylation (Leach et al., 2012); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27746744, 19779033, 8675635, 17039419, 24111791, 22798347, 19389809, 8878438, 17284438, 11013439, 11762699, 12890593, 23372019)
Fulgent Genetics, Fulgent Genetics	RCV002488857	SCV002804104	likely pathogenic	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2022-05-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401408	SCV004122104	likely pathogenic	Familial hypocalciuric hypercalcemia	2023-10-25	criteria provided, single submitter	clinical testing	Variant summary: CASR c.2449G>A (p.Val817Ile) results in a conservative amino acid change located in the receptor calcium binding region (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251330 control chromosomes (gnomAD). c.2449G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (examples: Pearce_ 1995 and Vargas-Poussou_ 2016). These data indicate that the variant is likely to be associated with disease. Multiple studies have shown this variant leads to reduced cell surface expression, reduced Ca2+ sensitivity and reduced ERK1/2 phosphorylation compared to wild type (examples: Pearce_1996, Hu_2005, Huang_2007, Leach_2013, White_2018). The following publications have been ascertained in the context of this evaluation (PMID: 8675635, 17284438, 8878438, 15591042, 19389809, 26963950, 23372019). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.