ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.1164G>T (p.Leu388Phe) (rs763059359)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188365 SCV000241977 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted p.Leu388Phe (TTG>TTT):c.1164 G>T in exon 1 of the PCDH19 gene (NM_001105243.1). The Leu388Phe missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Leu388Phe in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. This amino acid substitution is conservative, as Leucine and Phenylalanine are both uncharged, non-polar amino acids. Leu388Phe alters a highly conserved position in the fourth Cadherin repeat of the protein, and other missense mutations have been reported in this region of the protein in association with PCDH19-related disorders. Multiple in silico algorithms predict Leu388Phe may be damaging to protein structure. Therefore, based on the currently available information, it is unclear whether Leu388Phe is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae RCV000692886 SCV000820734 uncertain significance Early infantile epileptic encephalopathy 9 2018-01-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 388 of the PCDH19 protein (p.Leu388Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs763059359, ExAC 0.004%). This variant has not been reported in the literature in individuals with PCDH19-related disease. ClinVar contains an entry for this variant (Variation ID: 206328). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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