rs142745096
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2PP5BS1_Supporting
The NM_000388.4(CASR):āc.848T>Cā(p.Ile283Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,614,100 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I283I) has been classified as Likely benign.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.848T>C | p.Ile283Thr | missense_variant | 4/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.848T>C | p.Ile283Thr | missense_variant | 4/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.848T>C | p.Ile283Thr | missense_variant | 4/7 | 1 | |||
CASR | ENST00000638421.1 | c.848T>C | p.Ile283Thr | missense_variant | 4/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.848T>C | p.Ile283Thr | missense_variant | 3/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251332Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135858
GnomAD4 exome AF: 0.0000677 AC: 99AN: 1461894Hom.: 1 Cov.: 34 AF XY: 0.0000619 AC XY: 45AN XY: 727248
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74366
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 20, 2023 | PP2, PS4_moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 04, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 28, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 15, 2015 | The I283T missense variant in the CASR gene has been reported previously in association with a CASR-related disorder (Guarnieri et al., 2010). Functional analysis showed impaired maturation, cell surface expression, and signaling of the I283T mutant protein compared with wild type. We interpret the I283T variant as pathogenic. - |
Familial hypocalciuric hypercalcemia 1 Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Nov 08, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 03, 2023 | Variant summary: CASR c.848T>C (p.Ile283Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia (0.0001 vs 0.005), allowing no conclusion about variant significance. c.848T>C has been reported in the literature in at least one heterozygous individual affected with primary hyperparathyroidism (e.g. Guarnieri_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypocalciuric Hypercalcemia. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g.Guarnieri_2010). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Nephrolithiasis/nephrocalcinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 05, 2023 | The p.I283T variant (also known as c.848T>C), located in coding exon 3 of the CASR gene, results from a T to C substitution at nucleotide position 848. The isoleucine at codon 283 is replaced by threonine, an amino acid with similar properties. This variant has been detected in an individual with primary hyperparathyroidism and reported to impair cell surface expression and signaling (Guarnieri V et al. J. Clin. Endocrinol. Metab., 2010 Apr;95:1819-29). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
CASR-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 27, 2023 | The CASR c.848T>C variant is predicted to result in the amino acid substitution p.Ile283Thr. This variant was reported in a 56-year-old woman with primary hyperparathyroidism (PHPT); functional analysis showed that this variant impaired the protein maturation, cell surface expression, and signaling (Guarnieri et al. 2010. PubMed ID: 20164288) and in an individual with kidney stone disease (Table S1, Anderegg et al. 2023. https://www.medrxiv.org/content/10.1101/2023.07.23.23292924v2.full). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 28, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 283 of the CASR protein (p.Ile283Thr). This variant is present in population databases (rs142745096, gnomAD 0.02%). This missense change has been observed in individual(s) with primary hyperparathyroidism (PMID: 20164288). ClinVar contains an entry for this variant (Variation ID: 410355). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 20164288). 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. - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Mar 21, 2022 | ACMG categories: PM2,PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at