Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000545814 | SCV000638082 | uncertain significance | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2024-01-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 260 of the CASR protein (p.Gln260Arg). This variant is present in population databases (rs200386687, gnomAD 0.02%). 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: 463955). 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 tolerated. 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 | RCV002438358 | SCV001189271 | likely benign | Inborn genetic diseases; Nephrolithiasis/nephrocalcinosis | 2022-05-24 | criteria provided, single submitter | clinical testing | This alteration is classified as likely 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, |
RCV002483415 | SCV002787257 | uncertain significance | Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1 | 2022-02-19 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003387878 | SCV004099635 | likely benign | not specified | 2023-09-08 | criteria provided, single submitter | clinical testing | Variant summary: CASR c.779A>G (p.Gln260Arg) results in a conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251360 control chromosomes (gnomAD). The observed variant frequency is approximately 99 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASR causing Autosomal Dominant Hypocalcemia phenotype (1.3e-06), strongly suggesting that the variant is benign. c.779A>G has been reported in the literature in one individual affected with cystic fibrosis (Gaitch_2016). The report does not provide unequivocal conclusions about association of the variant with Autosomal Dominant Hypocalcemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27086061). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. |
| Department of Pathology and Laboratory Medicine, |
RCV001357374 | SCV001552831 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The CASR p.Gln260Arg variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200386687) and in ClinVar (classified as a VUS by Invitae for hypercalcemia, autosomal dominant 1). The variant was identified in control databases in 32 of 282768 chromosomes at a frequency of 0.000113 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 26 of 129098 chromosomes (freq: 0.000201), Other in 1 of 7218 chromosomes (freq: 0.000139), South Asian in 3 of 30616 chromosomes (freq: 0.000098), African in 1 of 24952 chromosomes (freq: 0.00004) and European (Finnish) in 1 of 25124 chromosomes (freq: 0.00004); it was not observed in the Latino, Ashkenazi Jewish and East Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gln260 residue is conserved in mammals however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |