ClinVar Miner

Submissions for variant NM_212472.2(PRKAR1A):c.623del (p.Gly208fs) (rs727503379)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151681 SCV000199987 pathogenic Carney complex 2014-06-09 criteria provided, single submitter clinical testing The Gly208fs variant in PRKAR1A has been previously reported in one family with Carney complex (Casey 1998, Casey 2000) but was absent from large population stu dies. This frameshift variant is predicted to alter the protein?s amino acid seq uence beginning at position 208 and lead to a premature termination codon 14 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. This prediction is further supported by functional analyses (Ca sey 2000). Loss of function of the PRKAR1A gene is an established disease mechan ism in individuals with Carney complex (Kirschner, 2000). In summary, this varia nt meets our criteria to be classified as pathogenic ( LMM).
GeneDx RCV000317950 SCV000329474 pathogenic not provided 2016-07-14 criteria provided, single submitter clinical testing The c.623delG variant in the PRKAR1A gene has been reported previously in association Carney complex, where it was shown to result in decreased R1α protein in lymphocytes (Casey et al., 2000). The c.623delG deletion causes a frameshift starting with codon Glycine 208 , changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Gly208GlufsX14. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the c.623delG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, we consider c.623delG to be a pathogenic variant.

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