ClinVar Miner

Submissions for variant NM_000228.3(LAMB3):c.1705C>T (p.Arg569Ter) (rs201551805)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169086 SCV000220263 likely pathogenic Junctional epidermolysis bullosa gravis of Herlitz 2014-04-23 criteria provided, single submitter literature only
GeneDx RCV000254699 SCV000321862 pathogenic not provided 2021-02-17 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 8824879, 29334134, 28087116, 15725250, 11023379, 12813757, 9160387, 32484238)
Invitae RCV000254699 SCV000931385 pathogenic not provided 2019-05-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg569*) in the LAMB3 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs201551805, ExAC 0.01%). This variant has been reported in several individuals affected with junctional epidermolysis bullosa (PMID: 8824879, 11023379). ClinVar contains an entry for this variant (Variation ID: 188764). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in LAMB3 are known to be pathogenic (PMID: 11023379, 16473856). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169086 SCV001362892 pathogenic Junctional epidermolysis bullosa gravis of Herlitz 2019-09-30 criteria provided, single submitter clinical testing Variant summary: LAMB3 c.1705C>T (p.Arg569X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.2e-05 in 249462 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LAMB3 causing Junctional Epidermolysis Bullosa (5.2e-05 vs 0.00093). c.1705C>T has been reported in the literature in individuals affected with Junctional Epidermolysis Bullosa (Kivirikko_1996, Fassihi_2004, Lucky_2018). Yenamandra_2017 reported the variant in homozygous state in a patient with Generalized Severe JEB and a poor prognosis, with strongly reduced staining for laminin-332 noted following immunofluorescence antigen mapping. These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000169086 SCV001523008 pathogenic Junctional epidermolysis bullosa gravis of Herlitz 2020-09-11 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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