Submissions for variant NM_000228.3(LAMB3):c.727C>T (p.Gln243Ter)

gnomAD frequency: 0.00005  dbSNP: rs80356681

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578876	SCV000680542	pathogenic	not provided	2023-09-13	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, 34426522, 34582790, 17000025, 27913086, 9326326, 8824879)
Myriad Genetics, Inc.	RCV000020223	SCV001194170	likely pathogenic	Junctional epidermolysis bullosa gravis of Herlitz	2019-12-09	criteria provided, single submitter	clinical testing	NM_000228.2(LAMB3):c.727C>T(Q243*) is classified as likely pathogenic in the context of Herlitz junctional epidermolysis bullosa, LAMB3-related. Sources cited for classification include the following: PMID 11023379, 8983017, 12813757, 16473856, 9326326 and 8824879. Classification of NM_000228.2(LAMB3):c.727C>T(Q243*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000578876	SCV001204499	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln243*) 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 (rs80356681, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with junctional epidermolysis bullosa (PMID: 8824879, 9326326). ClinVar contains an entry for this variant (Variation ID: 35480). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201255	SCV001372357	pathogenic	Junctional epidermolysis bullosa	2020-06-08	criteria provided, single submitter	clinical testing	Variant summary: LAMB3 c.727C>T (p.Gln243X) 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 been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251416 control chromosomes (gnomAD). c.727C>T has been reported in the literature, in the compound heterozygous or homozygous state, in multiple individuals affected with Junctional Epidermolysis Bullosa (e.g. Hammersen_2016, Kivirikko_1996, Pfender_2003, Robbins_2001). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394172	SCV006057209	pathogenic	Amelogenesis imperfecta type 1A; Junctional epidermolysis bullosa gravis of Herlitz; Junctional epidermolysis bullosa, non-Herlitz type	2022-05-03	criteria provided, single submitter	research
GeneReviews	RCV000020223	SCV000040566	not provided	Junctional epidermolysis bullosa gravis of Herlitz		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000578876	SCV001744112	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000578876	SCV001927312	pathogenic	not provided		no assertion criteria provided	clinical testing