ClinVar Miner

Submissions for variant NM_000228.3(LAMB3):c.463dup (p.Ser155fs)

gnomAD frequency: 0.00002  dbSNP: rs776537364
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169311 SCV000220633 likely pathogenic Junctional epidermolysis bullosa gravis of Herlitz 2014-08-25 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169311 SCV000919567 likely pathogenic Junctional epidermolysis bullosa gravis of Herlitz 2017-11-13 criteria provided, single submitter clinical testing Variant summary: The LAMB3 c.463dupT (p.Ser155PhefsX27) variant results in a premature termination codon, predicted to cause a truncated or absent LAMB3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1365_1366delCA, p.Asn456fsX7; c.1903C>T, p.Arg635X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/246120 control chromosomes at a frequency of 0.0000163, which does not exceed the estimated maximal expected allele frequency of a pathogenic LAMB3 variant (0.0009317). The variant has been reported in at least 3 affected individuals in the literature. In addition, one clinical diagnostic laboratory/reputable database classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000818902 SCV000959540 pathogenic not provided 2022-07-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser155Phefs*27) in the LAMB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMB3 are known to be pathogenic (PMID: 11023379, 16473856). This variant is present in population databases (rs776537364, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 8824879, 11023379; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188937). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002492690 SCV002790878 pathogenic Amelogenesis imperfecta type 1A; Junctional epidermolysis bullosa gravis of Herlitz; Junctional epidermolysis bullosa, non-Herlitz type 2022-03-21 criteria provided, single submitter clinical testing

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