Submissions for variant NM_000228.3(LAMB3):c.2842del (p.Val948fs)

dbSNP: rs772421306

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413231	SCV000490597	pathogenic	not provided	2016-02-08	criteria provided, single submitter	clinical testing	The c.2842delG pathogenic variant in the LAMB3 gene has been reported previously in thehomozygous or compound heterozygous state in patients with Herlitz JEB (Varki et al., 2006;Kittridge et al., 2014). The deletion causes a frameshift starting with codon Valine 948, changes this amino acid to a Cysteine residue and creates a premature Stop codon at position 82 of the new reading frame, denoted p.Val948CysfsX82. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the c.2842delG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2842delG as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780371	SCV000917570	pathogenic	Junctional epidermolysis bullosa, non-Herlitz type	2018-11-09	criteria provided, single submitter	clinical testing	Variant summary: LAMB3 c.2842delG (p.Val948CysfsX82) 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 1.8e-05 in 277164 control chromosomes (gnomAD). The variant, c.2842delG, has been reported in the literature in individuals affected with Herlitz Junctional Epidermolysis Bullosa (Kittridge_2014, Varki_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000413231	SCV000938577	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val948Cysfs*82) 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 (rs772421306, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with Herlitz junctional epidermolysis bullosa (PMID: 16473856). ClinVar contains an entry for this variant (Variation ID: 372403). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000984194	SCV001162871	pathogenic	Junctional epidermolysis bullosa gravis of Herlitz		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481270	SCV002780325	pathogenic	Amelogenesis imperfecta type 1A; Junctional epidermolysis bullosa gravis of Herlitz; Junctional epidermolysis bullosa, non-Herlitz type	2021-10-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000984194	SCV001132245	likely pathogenic	Junctional epidermolysis bullosa gravis of Herlitz	2015-03-19	no assertion criteria provided	clinical testing