Submissions for variant NM_001184880.2(PCDH19):c.409G>T (p.Glu137Ter)

dbSNP: rs1555985689

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497495	SCV000589700	likely pathogenic	not provided	2015-12-04	criteria provided, single submitter	clinical testing	The E137X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E137X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, multiple downstream nonsense variants have been reported in Human Gene Mutation Database in association with PCDH19-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865562	SCV002135254	pathogenic	Developmental and epileptic encephalopathy, 9	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu137*) in the PCDH19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH19 are known to be pathogenic (PMID: 21053371). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with epilepsy with or without neurodevelopmental disorder (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 432030). For these reasons, this variant has been classified as Pathogenic.