Submissions for variant NM_000388.4(CASR):c.1297G>C (p.Asp433His)

gnomAD frequency: 0.00001  dbSNP: rs199511990

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002231730	SCV000638012	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 433 of the CASR protein (p.Asp433His). This variant is present in population databases (rs199511990, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with tropical chronic pancreatitis (PMID: 18938753). ClinVar contains an entry for this variant (Variation ID: 463897). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002384117	SCV002692409	benign	Inborn genetic diseases; Nephrolithiasis/nephrocalcinosis	2023-02-02	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002476144	SCV002782493	uncertain significance	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2021-08-31	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003448320	SCV004176357	uncertain significance	Familial hypocalciuric hypercalcemia 1	2023-02-14	criteria provided, single submitter	clinical testing	The missense variant c.1297G>C (p.Asp433His) in the CASR gene has been reported previously in heterozygous state in individuals affected with Tropical Calcific Pancreatitis (TCP). Molecular dynamics simulation, along with essential dynamics analysis indicates that the mutation D433H has a significant impact on protein structure (Shrivastava et al., 2022; Murugaian et al., 2008). This variant is reported with the allele frequency (0.02%) in the gnomAD and novel in 1000 genome database. It is submitted to ClinVar as Uncertain significance. The amino acid Aspartic Acid at position 433 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Asp433His in CASR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Although this variant has a higher MAF, based on molecular dynamics and clinvar reports, this variant is classified as Variant of uncertain significance. Classification is likely to change as more literature becomes available.
PreventionGenetics, part of Exact Sciences	RCV003900163	SCV004715300	likely benign	CASR-related condition	2022-03-07	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).