ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.220A>G (p.Met74Val)

dbSNP: rs745377913
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001980365 SCV002272691 uncertain significance Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2021-11-07 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 74 of the CASR protein (p.Met74Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypocalciuric hypercalcemia type 1 or primary hyperparathyroidism (PMID: 26963950, 32347971). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004782848 SCV005394011 uncertain significance not specified 2024-09-04 criteria provided, single submitter clinical testing Variant summary: CASR c.220A>G (p.Met74Val) results in a conservative amino acid change located in the Receptor, ligand binding domain (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251342 control chromosomes. c.220A>G has been reported in the literature in heterozygous individuals affected with Autosomal Dominant Hypocalcemia (Vargas-Poussou_2016, Mouly_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32347971, 26963950). ClinVar contains an entry for this variant (Variation ID: 1488908). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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