ClinVar Miner

Submissions for variant NM_002734.4(PRKAR1A):c.545C>T (p.Thr182Met) (rs199801675)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493890 SCV000582195 likely pathogenic not provided 2015-10-20 criteria provided, single submitter clinical testing The T182M variant in the PRKAR1 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The T182M variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T182M variant 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 not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. One missense variant in a nearby residue (D183Y) has been reported in the Human Gene Mutation Database in association with Carney complex (Stenson et al., 2014). The T182M variant is a strong candidate for a pathogenic variant , however the possibility it may be a rare benign variant cannot be excluded
Invitae RCV000692010 SCV000819815 uncertain significance Carney complex, type 1 2018-02-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 182 of the PRKAR1A protein (p.Thr182Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs199801675, ExAC 0.01%). This variant has not been reported in the literature in individuals with PRKAR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 429590). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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