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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029439 SCV000052089 pathogenic Neonatal severe hyperparathyroidism 2020-10-28 criteria provided, single submitter clinical testing Variant summary: CASR c.206G>A (p.Arg69His) results in a non-conservative amino acid change located in the Receptor, ligand binding region domain (IPR001828) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251300 control chromosomes (gnomAD). c.206G>A has been reported in the literature in the homozygous or compound heterozygous state in individuals affected with Neonatal Severe Hyperparathyroidism (e.g. Wilhelm-Bals_2012, Corrado_2015, Murphy_2016), while it has also been reported in the heterozygous state in individuals affected with Familial Hypocalciuric Hypercalcemia (e.g. Wolf_2014, Corrado_2015, Vargas-Poussou_2016, Hureaux_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000465400 SCV000550954 uncertain significance Familial hypocalciuric hypercalcemia; Hypocalcemia, autosomal dominant 1 2020-10-25 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, 31672324) 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.
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.

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