Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000255633 | SCV000321861 | pathogenic | not provided | 2023-06-21 | criteria provided, single submitter | clinical testing | Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11810295, 28561256, 31001817) |
| Illumina Laboratory Services, |
RCV000778964 | SCV000915391 | likely pathogenic | Junctional epidermolysis bullosa | 2017-08-18 | criteria provided, single submitter | clinical testing | The LAMB3 c.1132+5G>A variant has been reported in two studies in which it is found in a total of four individuals with junctional epidermolysis bullosa including in a homozygous state in two twins and in a compound heterozygous state in two unrelated individuals (Nakano et al. 2002; Condorelli et al. 2017). One of the compound heterozygotes carries a null allele on the second allele. Control data are unavailable for this variant, which is reported at a frequency of 0.000054 in the European (non-Finnish) population of the Genome Aggregation Database. Expression studies using RT-PCR demonstrated that the c.1132+5G>A variant resulted in the production of two major aberrant transcripts with partial skipping of the exon 10 of the LAMB3 gene coding for EGF-like motif 2 of the beta3 short arm of laminin-332 (Condorelli et al. 2017). Although the laminin-332 protein was correctly assembled, it was retained in the endoplasmic reticulum (ER) where it co-localization with lumenal ER chaperone BiP, leading to significantly reduced secretion (Condorelli et al. 2017). Based on the collective evidence, the c.1132+5G>A variant is classified as likely pathogenic for junctional epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Labcorp Genetics |
RCV000255633 | SCV001585616 | pathogenic | not provided | 2023-12-09 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 10 of the LAMB3 gene. It does not directly change the encoded amino acid sequence of the LAMB3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs770302956, gnomAD 0.005%). This variant has been observed in individuals with autosomal recessive junctional epidermolysis bullosa (PMID: 11810295, 28561256). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265229). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 28561256). For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002494799 | SCV002779449 | pathogenic | Amelogenesis imperfecta type 1A; Junctional epidermolysis bullosa gravis of Herlitz; Junctional epidermolysis bullosa, non-Herlitz type | 2022-04-07 | criteria provided, single submitter | clinical testing |