rs1060502176
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001184880.2(PCDH19):c.707C>T(p.Pro236Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P236R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001184880.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH19 | NM_001184880.2 | c.707C>T | p.Pro236Leu | missense_variant | 1/6 | ENST00000373034.8 | |
PCDH19 | NM_001105243.2 | c.707C>T | p.Pro236Leu | missense_variant | 1/5 | ||
PCDH19 | NM_020766.3 | c.707C>T | p.Pro236Leu | missense_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH19 | ENST00000373034.8 | c.707C>T | p.Pro236Leu | missense_variant | 1/6 | 1 | NM_001184880.2 | A1 | |
PCDH19 | ENST00000255531.8 | c.707C>T | p.Pro236Leu | missense_variant | 1/5 | 1 | P5 | ||
PCDH19 | ENST00000420881.6 | c.707C>T | p.Pro236Leu | missense_variant | 1/5 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 24
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 9 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 236 of the PCDH19 protein (p.Pro236Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 26993267). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 626145). 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. This variant disrupts the p.Pro236 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31487502; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | PCDH19 NM_001184880.1 exon 1 p.Pro236Leu (c.707C>T): This variant has been reported in the literature as de novo in 1 individual with early infantile epileptic encephalopthy (Trump 2016 PMID:26993267). This variant is not present in large control databases. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, an additional variant at this codon (p.Pro236Ser) has been reported as de novo and in association with disease, supporting that this region has signifiance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Feb 27, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | not provided | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at