ClinVar Miner

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

dbSNP: rs193922433
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029440 SCV000052090 likely pathogenic Familial hypocalciuric hypercalcemia 2023-10-19 criteria provided, single submitter clinical testing Variant summary: CASR c.2243C>A (p.Pro748Gln) 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. A discrepancy between the genome and transcript sequences at the adjacent position c.2244 of this codon results in the minor allele, namely "C" at this location. As majority of occurrences have a "C" at this location, this variant can also be annotated as c.2243_2244delinsAC or as c.2243C>A, both of which encode p.Pro748His. A different variant, c.2243C>G (p.Pro748Arg) at the same location has been classified as pathogenic, supporting the critical relevance of this residue to protein function. The variant was absent in 250560 control chromosomes. c.2243C>A encoding p.Pro748His, has been reported in the literature in heterozygous individuals affected with Familial Hypocalciuric Hypercalcemia (e.g. Mouly_2020, Cetani_2009). To our knowledge, no reports of this variant encoding p.Pro748Gln have been reported in the literature. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact of p.Pro748His on protein function. The most pronounced variant effect results in >50%-90% of normal activity (e.g.Cetani_2009). The following publications have been ascertained in the context of this evaluation (PMID: 32347971, 19073830). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029440 SCV000052091 likely pathogenic Familial hypocalciuric hypercalcemia 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
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.

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