ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.2243C>A (p.Pro748Gln) (rs193922433)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478953 SCV000574160 likely pathogenic not provided 2017-03-10 criteria provided, single submitter clinical testing The P748H variant has been published previously in association with familial hypocalciuric hypercalcemia (Cetani et al. 2009). It is reported as likely pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000052090.1; Landrum et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). P748H is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies have shown the P748H receptor shows a reduced response to calcium in comparison to wild type (Cetani et al. 2009). In summary, this variant is likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000029440 SCV000052090 likely pathogenic Familial hypocalciuric hypercalcemia 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000029440 SCV000052091 likely pathogenic Familial hypocalciuric hypercalcemia 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV000800266 SCV000939969 uncertain significance Familial hypocalciuric hypercalcemia; Hypocalcemia, autosomal dominant 1 2018-09-18 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 748 of the CASR protein (p.Pro748His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with hypocalciuric hypercalcemia (PMID: 19073830). ClinVar contains an entry for this variant (Variation ID: 35788). Experimental studies have shown that this missense affects CASR protein function (PMID: 19073830). 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.

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