ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.1376A>G (p.Gln459Arg)

dbSNP: rs2107633334
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001379696 SCV001577542 pathogenic Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2023-09-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects CASR function (PMID: 19789209, 24517148, 27666534, 32160303). 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. ClinVar contains an entry for this variant (Variation ID: 1068215). This missense change has been observed in individuals with familial hypocalciuric hypercalcemia (PMID: 19789209, 24517148, 32160303). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 459 of the CASR protein (p.Gln459Arg).
Athena Diagnostics RCV001664859 SCV001879545 pathogenic not provided 2021-03-23 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Many reported carriers of this variant presented with a mild phenotype of hypercalcemia and/or hypocalciuria (PMID: 19789209, 32160303, 24517148). This variant associates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Study showed mild impaired calcium function (PMID: 19789209,32160303, 24517148, 27666534). Computational tools predict that this variant is damaging. Computational tools yielded predictions that this variant may interfere with normal RNA splicing.
Clinical Genetics Laboratory, Skane University Hospital Lund RCV001664859 SCV005197387 pathogenic not provided 2022-07-13 criteria provided, single submitter clinical testing

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