ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.1019A>C (p.Asn340Thr)

dbSNP: rs796052839
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494063 SCV000582703 likely pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the PCDH19 gene. The N340T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different substitution at the same position (N340S) has been reported previously multiple times in association with PCDH19-related disorders (Depienne et al., 2009; Depienne et al., 2012). The N340T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the N340T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001348836 SCV001543154 likely pathogenic Developmental and epileptic encephalopathy, 9 2022-11-29 criteria provided, single submitter clinical testing 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. This variant disrupts the p.Asn340 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19214208, 20713952, 21480887, 21519002). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt PCDH19 protein function. ClinVar contains an entry for this variant (Variation ID: 429996). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 340 of the PCDH19 protein (p.Asn340Thr).

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