ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.695A>G (p.Asn232Ser) (rs587784299)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720069 SCV000850945 likely pathogenic History of neurodevelopmental disorder 2017-08-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000641136 SCV000898867 pathogenic Early infantile epileptic encephalopathy 9 2018-08-31 criteria provided, single submitter clinical testing PCDH19 NM_001184880.1 exon 1 p.Asn232Ser (c.695A>G): This variant has been reported in the literature in 6 affected individuals with epilepsy, including 3 individuals further characterized with Dravet syndrome (Depienne 2012 PMID:22267240, Marini 2012 PMID:22946748, Gaily 2013 PMID:23808377, Breuillard 2016 PMID:27179713, Liu 2017 PMID:27527380, Smith 2018 PMID:29377098). The variant was reported to be de novo in 4 of these 6 individuals (Marini 2012 PMID:22946748, Gaily 2013 PMID:23808377, Liu 2017 PMID:27527380, Smith 2018 PMID:29377098). This variant is not present in large control databases, and it is present in ClinVar (Variation ID:206321). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic.
GeneDx RCV000188357 SCV000241969 pathogenic not provided 2015-06-23 criteria provided, single submitter clinical testing This variant is denoted p.Asn232Ser (AAT>AGT): c.695 A>G in exon 1 of the PCDH19 gene (NM_001105243.1). The N232S missense substitution in the PCDH19 gene has been published as a de novo mutation in a female with Dravet syndrome and was also reported in another female with epilepsy (Gaily et al., 2013; Depienne et al., 2012). It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a conserved position in the cadherin 2 domain of the protein. N232S is considered a pathogenic mutation, and its presence is consistent with a diagnosis of a PCDH19-related disorder. The variant is found in EPILEPSY,INFANT-EPI panel(s).
Invitae RCV000641136 SCV000762758 pathogenic Early infantile epileptic encephalopathy 9 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 232 of the PCDH19 protein (p.Asn232Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in several female individuals affected with Dravet syndrome (PMID: 23808377, 27527380) and epilepsy (PMID: 22946748). It has also been found in a female with epilepsy and intellectual disability (PMID: 22267240). ClinVar contains an entry for this variant (Variation ID: 206321). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

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