rs797045841
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001205254.2(OCLN):c.173_194del(p.Trp58PhefsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
OCLN
NM_001205254.2 frameshift
NM_001205254.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.81
Genes affected
OCLN (HGNC:8104): (occludin) This gene encodes an integral membrane protein that is required for cytokine-induced regulation of the tight junction paracellular permeability barrier. Mutations in this gene are thought to be a cause of band-like calcification with simplified gyration and polymicrogyria (BLC-PMG), an autosomal recessive neurologic disorder that is also known as pseudo-TORCH syndrome. Alternative splicing results in multiple transcript variants. A related pseudogene is present 1.5 Mb downstream on the q arm of chromosome 5. [provided by RefSeq, Apr 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-69509260-AATGGACCTCTCCTCCAGGAGTG-A is Pathogenic according to our data. Variant chr5-69509260-AATGGACCTCTCCTCCAGGAGTG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211775.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1}. Variant chr5-69509260-AATGGACCTCTCCTCCAGGAGTG-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OCLN | NM_001205254.2 | c.173_194del | p.Trp58PhefsTer10 | frameshift_variant | 3/9 | ENST00000396442.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OCLN | ENST00000396442.7 | c.173_194del | p.Trp58PhefsTer10 | frameshift_variant | 3/9 | 1 | NM_001205254.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Pseudo-TORCH syndrome 1 Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 23, 2015 | - - |
Uncertain significance, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The homozygous p.Trp58PhefsTer10 variant in OCLN was identified by our study in one individual with pseudo-torch syndrome. This variant was absent from large population studies. The homozygous variant was also reported in two Turkish siblings with pseudo-torch syndrome (PMID: 20727516). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 58 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. At least two loss of function variants across multiple exons have been reported in association with pseudo-torch syndrome in ClinVar. Loss of function of the OCLN gene is a moderately established disease mechanism in autosomal recessive pseudo-torch syndrome. O'Driscoll et al. reported that five out of the six families with pseudo-torch syndrome in their study had variants that impacted the conserved MARVEL protein domain, which is associated with localization to the cellular membrane (PMID: 20727516). This suggests that variants in the MARVEL domain may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PVS1_Moderate, PM1_Supporting (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Jan 01, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at