ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.206G>A (p.Arg69His) (rs193922432)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000518959 SCV000617657 likely pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing The R69H variant in the CASR gene has previously been reported in association with familial hypocalciuric hypercalcemia and neonatal severe primary hyperparathyroidism (Wilhelm-Bals et al., 2012; Wolf et al., 2014; Corrado et al., 2015; Murphy et al., 2016). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R69H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar 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. Based on the currently available information, R69H is a strong candidate for a pathogenic variant. However, the possibility that it may be a rare benign variant cannot be excluded.
Integrated Genetics/Laboratory Corporation of America RCV000029439 SCV000052089 likely pathogenic Familial hypocalciuric hypercalcemia 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV000465400 SCV000550954 uncertain significance Hypocalciuric hypercalcemia, familial, type 1; Hypocalcemia, autosomal dominant 1 2017-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 69 of the CASR protein (p.Arg69His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs193922432, ExAC 0.01%). This variant has been reported in individuals affected with familial hypocalciuric hypercalcemia (PMID: 24947037, 26963950) and neonatal primary hyperparathyroidism (PMID: 22331334, 26855056, 25828954). ClinVar contains an entry for this variant (Variation ID: 35787). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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