rs104893716
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong
The NM_000388.4(CASR):c.1394G>A(p.Arg465Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465W) has been classified as Pathogenic.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.1394G>A | p.Arg465Gln | missense_variant | 5/7 | ENST00000639785.2 | NP_000379.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.1394G>A | p.Arg465Gln | missense_variant | 5/7 | 1 | NM_000388.4 | ENSP00000491584.2 | ||
CASR | ENST00000498619.4 | c.1394G>A | p.Arg465Gln | missense_variant | 5/7 | 1 | ENSP00000420194.1 | |||
CASR | ENST00000638421.1 | c.1394G>A | p.Arg465Gln | missense_variant | 5/7 | 5 | ENSP00000492190.1 | |||
CASR | ENST00000490131.7 | c.1378-6285G>A | intron_variant | 5 | ENSP00000418685.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461146Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726980
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial hypocalciuric hypercalcemia 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 14, 2006 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, Biobizkaia Health Research Institute | Mar 08, 2024 | - - |
Nephrolithiasis/nephrocalcinosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2024 | The p.R465Q variant (also known as c.1394G>A), located in coding exon 4 of the CASR gene, results from a G to A substitution at nucleotide position 1394. The arginine at codon 465 is replaced by glutamine, an amino acid with highly similar properties. This variant has been identified in individuals with hyperparathyroidism as well as individuals with familial hypocalciuric hypercalcemia (Leech C et al. Biochem. Biophys. Res. Commun., 2006 Apr;342:996-1002; Mayr B et al. Eur. J. Endocrinol., 2016 May;174:R189-208; Vargas-Poussou R et al. J. Clin. Endocrinol. Metab., 2016 05;101:2185-95; Szalat A et al. Endocrine, 2017 Mar;55:741-747Asla Q et al. Endocrine, 2024 Mar;83:747-756; García-Castaño A et al. Front Endocrinol (Lausanne), 2024 Mar;15:1297614). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, the evidence for the gene-disease relationship is limited for pancreatitis and cancer predisposition; therefore, the clinical significance of this variant for CASR-related pancreatitis and cancer predisposition is unclear. Based on the supporting evidence, this variant is likely pathogenic for FHH1; however, the association of this variant with ADH1 is unlikely. - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 465 of the CASR protein (p.Arg465Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with benign familial hypocalciuric hypercalcemia (PMID: 16598859, 26646938, 26963950, 28176280, 30407919; Invitae). ClinVar contains an entry for this variant (Variation ID: 8352). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 16598859). This variant disrupts the p.Arg465 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20164288, 29026550, 31672324; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 30, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 07, 2023 | This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant hypocalciuric hypercalcemia. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 16598859) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at