ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.1114C>T (p.Arg372Trp) (rs796052812)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188364 SCV000241976 pathogenic not provided 2014-04-24 criteria provided, single submitter clinical testing This variant is denoted p.Arg372Trp (CGG>TGG): c.1114 C>T in exon 1 of the PCDH19 gene (NM_001105243.1). The R372W missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. However, the R372W missense substitution has been seen in other unrelated individuals at GeneDX. The NHLBI ESP Exome Variant Project has not identified R372W in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. R372W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. It alters a highly conserved position in the fourth extracellular cadherin domain of the protein, and multiple mutations in this domain have been published in association with epilepsy (Marini et al., 2010). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the R372W missense substitution is considered a disease-causing mutation consistent with a diagnosis of a PCDH19-related disorder. The variant is found in EPILEPSY panel(s).
Invitae RCV000698779 SCV000827465 likely pathogenic Early infantile epileptic encephalopathy 9 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 372 of the PCDH19 protein (p.Arg372Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in two individuals affected with epilepsy (PMID: 29377098, Invitae). ClinVar contains an entry for this variant (Variation ID: 206327). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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