ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.224A>G (p.Asn75Ser)

gnomAD frequency: 0.00004  dbSNP: rs796052790
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188327 SCV000241939 uncertain significance not provided 2019-08-16 criteria provided, single submitter clinical testing The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV000764882 SCV000896039 uncertain significance Developmental and epileptic encephalopathy, 9 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000764882 SCV001510994 uncertain significance Developmental and epileptic encephalopathy, 9 2023-10-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 75 of the PCDH19 protein (p.Asn75Ser). This variant is present in population databases (rs796052790, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. ClinVar contains an entry for this variant (Variation ID: 206292). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCDH19 protein function. 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.
Genetic Services Laboratory, University of Chicago RCV001818456 SCV002070047 uncertain significance not specified 2020-01-09 criteria provided, single submitter clinical testing DNA sequence analysis of the PCDH19 gene demonstrated a sequence change, c.224A>G, in exon 1 that results in an amino acid change, p.Asn75Ser. This sequence change does not appear to have been previously described in patients with PCDH19-related disorders. This particular sequence change has been described in the gnomAD database in two individuals in the hemizygous state which corresponds to a population frequency of 0.00099% (dbSNP rs796052790). The p.Asn75Ser change affects a moderately conserved amino acid residue located in a domain of the PCDH19 protein that is known to be functional. The p.Asn75Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn75Ser change remains unknown at this time.
Neurogenetics Research Program, University of Adelaide RCV001199411 SCV001147045 benign Neurodevelopmental disorder with epilepsy 2019-12-20 no assertion criteria provided research

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