ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.1019A>G (p.Asn340Ser) (rs796052839)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188401 SCV000242013 pathogenic not provided 2017-08-10 criteria provided, single submitter clinical testing The N340S variant in the PCDH19 gene has been reported previously multiple times in association with PCDH19-related disorders (Depienne et al., 2009; Depienne et al., 2012). The N340S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N340S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, 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. Additionally, multiple missense variants in nearby residues have been reported in Human Gene Mutation Database in association with PCDH19-related disorders (Stenson et al., 2014). Therefore, we consider the N340S variant to be pathogenic.
Invitae RCV000560023 SCV000640252 pathogenic Early infantile epileptic encephalopathy 9 2019-10-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 340 of the PCDH19 protein (p.Asn340Ser). 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 individuals with early onset severe seizures (PMID: 19214208, 21480887, 20713952, 27527380, 22946748) and is recognized as one of the most common recurrent PCDH19 mutations identified in patients with epilepsy (PMID: 2267240, 23334464, 22848613). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It is absent from the general population and commonly found in individuals affected with PCDH19-related epilepsy. Therefore, this variant has been classified as Pathogenic.
Ambry Genetics RCV000720797 SCV000851681 pathogenic History of neurodevelopmental disorder 2017-05-08 criteria provided, single submitter clinical testing Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification

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