ClinVar Miner

Submissions for variant NM_005562.3(LAMC2):c.667C>T (p.Arg223Ter) (rs753268823)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169121 SCV000220330 likely pathogenic Junctional epidermolysis bullosa gravis of Herlitz 2014-05-20 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169121 SCV001362356 pathogenic Junctional epidermolysis bullosa gravis of Herlitz 2019-04-22 criteria provided, single submitter clinical testing Variant summary: LAMC2 c.667C>T (p.Arg223X) 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. Truncations downstream of this position have reported in patients in the literature (HGMD). The variant allele was found at a frequency of 4e-06 in 251492 control chromosomes (gnomAD). c.667C>T has been reported in the literature in a compound heterozygous patient who was affected by the most severe, Herlitz type of Junctional Epidermolysis Bullosa (Posteraro 2004, Castori 2008). One of these publications also reported that northern blot analysis of the patients RNA indicated the lack of WT mRNA, furthermore, the patient was negative for laminin-5 staining by immunofluorescence and had rudimentary hemidesmosomes by transmission electron microscopy (Posteraro 2004). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001201907 SCV001372999 pathogenic not provided 2019-09-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg223*) in the LAMC2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs753268823, ExAC 0.001%). This variant has been observed in combination with another LAMC2 variant in an individual affected with Junctional epidermolysis bullosa (PMID: 15373767). ClinVar contains an entry for this variant (Variation ID: 188791). Loss-of-function variants in LAMC2 are known to be pathogenic (PMID: 11907499, 16473856). For these reasons, this variant has been classified as Pathogenic.

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