Submissions for variant NM_000228.3(LAMB3):c.565-2A>G

gnomAD frequency: 0.00003  dbSNP: rs370148688

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169196	SCV000919568	pathogenic	Junctional epidermolysis bullosa gravis of Herlitz	2018-01-25	criteria provided, single submitter	clinical testing	Variant summary: The LAMB3 c.565-2A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the complete loss of a cannonical splice acceptor site. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 30936 control chromosomes and has been reported in affected individuals in the literature (Pulkkinen_1997, Varki_2006, Yuen_2011). In addition, one clinical diagnostic laboratory/reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812274	SCV000952583	pathogenic	not provided	2023-09-15	criteria provided, single submitter	clinical testing	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. This sequence change affects an acceptor splice site in intron 6 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 (rs370148688, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with epidermolysis bullosa (PMID: 9242513, 16473856, 21801158). ClinVar contains an entry for this variant (Variation ID: 188846).
GeneDx	RCV000812274	SCV001812850	pathogenic	not provided	2020-05-18	criteria provided, single submitter	clinical testing	Considered a recurrent variant accounting for 1-3% of mutant LAMB3 alleles among patients with JEB (Nakano et al., 2000; Varki et al., 2006); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21801158, 12813757, 16473856, 11023379, 9242513, 25525159)
Myriad Genetics, Inc.	RCV001810431	SCV002060383	pathogenic	Junctional epidermolysis bullosa gravis of Herlitz; Junctional epidermolysis bullosa, non-Herlitz type	2021-11-10	criteria provided, single submitter	clinical testing	NM_000228.2(LAMB3):c.565-2A>G is a canonical splice variant classified as pathogenic in the context of junctional epidermolysis bullosa, LAMB3-related. c.565-2A>G has been observed in cases with relevant disease (PMID: 9242513). Functional assessments of this variant are not available in the literature. c.565-2A>G has been observed in population frequency databases (gnomAD: OTH 0.01%). In summary, NM_000228.2(LAMB3):c.565-2A>G is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.