Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000411875 | SCV000485845 | likely pathogenic | Junctional epidermolysis bullosa gravis of Herlitz | 2016-02-24 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000523835 | SCV000617711 | pathogenic | not provided | 2017-08-07 | criteria provided, single submitter | clinical testing | The c.628+1G>A variant in the LAMB3 gene has been reported previously in association with non-lethel JEB ( Pulkkinen et al., 1995). This splice site variant destroys the canonical splice donor site in intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.628+1G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.628+1G>A as a pathogenic variant. |
Invitae | RCV000523835 | SCV002281502 | likely pathogenic | not provided | 2023-10-10 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 7 of the LAMB3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LAMB3 are known to be pathogenic (PMID: 11023379, 16473856). This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with epidermolysis bullosa (PMID: 7550237). ClinVar contains an entry for this variant (Variation ID: 370503). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002469140 | SCV002765973 | likely pathogenic | Junctional epidermolysis bullosa | 2022-11-28 | criteria provided, single submitter | clinical testing | Variant summary: LAMB3 c.628+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (example: Pulkkinen_1995). The variant was absent in 251490 control chromosomes (gnomAD). c.628+1G>A has been reported in the literature in at-least one individual affected with Junctional Epidermolysis Bullosa (example: Pulkkinen_1995). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |