ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.2243C>G (p.Pro748Arg)

dbSNP: rs193922433
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001205771 SCV001377045 uncertain significance Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2019-09-09 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 748 of the CASR protein (p.Pro748Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several families affected with familial hypocalciuric hypercalcemia and to segregate with disease in a family (PMID: 8636323, 26963950). This variant has also been observed in an individual affected with familial hypocalciuric hypercalcemia and primary hyperparathyroidism (PMID: 22232026). This variant has been reported to affect CASR protein function (PMID: 19389809, 22798347, 23372019). 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.
Athena Diagnostics Inc RCV001289357 SCV001477108 likely pathogenic not provided 2019-12-30 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Genetics and Molecular Pathology, SA Pathology RCV002272407 SCV002557009 pathogenic Familial hypocalciuric hypercalcemia 1 2023-07-19 criteria provided, single submitter clinical testing The CASR c.2243C>G variant is classified as Pathogenic (PS4_Moderate, PS3, PM2, PP3, PP1_Moderate) The CASR c.2243C>G variant is a single nucleotide change in exon 7/7 of the CASR gene, which is predicted to change the amino acid proline at position 748 in the protein to arginine. This variant is absent from population databases (PM2). It has been reported in the literature to segregate with disease in a family affected by FHH (PMID: 8636323) (PP1_Moderate) and has been detected in two unrelated individuals affected by FHH and PHPT (PMID: 22232026, 3237971) (PS4_Moderate). Functional studies suggest a detrimental effect on CASR protein function (PMID: 19389809, PMID: 22798347) and has been shown to alter binding affinity of allosteric modulators (PMID: 23372019) (PS3). Two other missense changes at codon 748 have also been reported in the literature in association with FHH (PMID: 19073830, 22422767). Computational predictions (REVEL = 0.951) support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs193922433) and in the HGMD database: CM962443. It has been reported as VUS and Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 936871).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323817 SCV004028641 pathogenic Familial hypocalciuric hypercalcemia 2023-07-24 criteria provided, single submitter clinical testing Variant summary: CASR c.2243C>G (p.Pro748Arg) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250768 control chromosomes. c.2243C>G has been reported in the literature in multiple individuals affected with Familial Hypocalciuric Hypercalcemia (example, Heath_1996, Hannan_2012, Eldeiry_2012, Vargas-Poussou_2016, Arshad_2021) at-least one of these reports included an individual affected with Familial Hypocalciuric Hypercalcemia (FHH) and Primary Hyperparathyroidism (Eldeiry_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, White__2009). The most pronounced variant effect results in impaired localization to plasma membrane and not trafficked to Golgi. The following publications have been ascertained in the context of this evaluation (PMID: 32892159, 22232026, 22422767, 8636323, 11013439, 17979873, 23372019, 11762699, 26963950, 19389809). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (LP, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

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