ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.296G>A (p.Cys99Tyr)

dbSNP: rs2147542235
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
New York Genome Center RCV001784157 SCV002025693 uncertain significance Developmental and epileptic encephalopathy, 9 2020-04-18 criteria provided, single submitter clinical testing The p.Cys99Tyr missense variant identified in PCDH19 has been reported in a seven year old female affected with clusters of focal motor seizures precipitated by fever [3]. The variant was also detected in her three unaffected relatives; father, paternal aunt and grandmother [PMID: 28199897]. A different missense variant (p.Cys99Ser) affecting the same Cys99 has been reported in the ClinVar [variation ID:421597]. The p.Cys99Tyr variant is absent from gnomAD database indicating that its an extremely rare allele in general population. The affected cystine residue is located in one of the six cadherin repeats [PMID: 30582250], is evolutionarily conserved, and predicted deleterious by multiple in silico prediction tools. However, due to the lack of functional studies, presence of p.Cys99Tyr in at least two asymptomatic females [PMID: 28199897], and detection of the variant in this individual’s asymptomatic mother, the p.Cys99Tyr variant in PCDH19 is assessed as a variant of uncertain significance.
GeneDx RCV004719174 SCV005324825 likely pathogenic not provided 2024-02-07 criteria provided, single submitter clinical testing Previously reported as a paternally inherited variant in a female with focal seizures; however the variant was also present in unaffected female relatives. (PMID: 28199897); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28199897)

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