ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.437C>G (p.Thr146Arg) (rs796052799)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188349 SCV000241961 likely pathogenic not provided 2016-08-16 criteria provided, single submitter clinical testing This variant is denoted p.Thr146Arg (ACG>AGG): c.437 C>G in exon 1 of the PCDH19 gene (NM_001105243.1). A T146R variant that is likely pathogenic has been identified in the PCDH19 gene. The T146R variant was reported previously in three sisters with febrile, generalized tonic-clonic and focal seizures and normal cognitive ability; the variant was inherited from their unaffected father (Depienne et al., 2011). It was not observed in approximately 6,300 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 T146R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, 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. Furthermore, a missense variant in a nearby residue (P149S) has been reported in the Human Gene Mutation Database in association with a PCDH19-related disorder (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

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