Submissions for variant NM_000388.4(CASR):c.848T>C (p.Ile283Thr)

gnomAD frequency: 0.00007  dbSNP: rs142745096

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000463689	SCV000550994	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-12-28	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000493534	SCV000582495	pathogenic	not provided	2015-09-15	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV004022778	SCV001179071	uncertain significance	Nephrolithiasis/nephrocalcinosis	2023-12-05	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000493534	SCV001250022	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV004584387	SCV002499655	uncertain significance	See cases	2022-03-21	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PP3
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268085	SCV002550875	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000493534	SCV002771681	uncertain significance	not provided	2021-09-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002268085	SCV004223022	uncertain significance	not specified	2023-11-03	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000493534	SCV004226145	uncertain significance	not provided	2023-04-20	criteria provided, single submitter	clinical testing	PP2, PS4_moderate
Revvity Omics, Revvity	RCV000493534	SCV004234949	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554781	SCV004742640	uncertain significance	CASR-related disorder	2023-11-27	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001030008	SCV004806423	likely pathogenic	Familial hypocalciuric hypercalcemia 1	2024-03-25	criteria provided, single submitter	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV001030008	SCV001192811	uncertain significance	Familial hypocalciuric hypercalcemia 1	2019-11-08	no assertion criteria provided	clinical testing