ClinVar Miner

Submissions for variant NM_000228.3(LAMB3):c.628+1G>A

gnomAD frequency: 0.00001  dbSNP: rs1057516539
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Total submissions: 4
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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
GeneDx 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, LabCorp 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.

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