Submissions for variant NM_000228.3(LAMB3):c.2914C>T (p.Arg972Ter)

gnomAD frequency: 0.00003  dbSNP: rs747916314

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522804	SCV000616763	pathogenic	not provided	2020-11-18	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, 28830826, 24617447, 9242513, 12813757)
Invitae	RCV000522804	SCV001210477	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg972*) 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 (rs747916314, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive junctional epidermolysis bullosa (PMID: 9242513, 28830826). ClinVar contains an entry for this variant (Variation ID: 449050). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468942	SCV001362890	pathogenic	Junctional epidermolysis bullosa	2022-11-03	criteria provided, single submitter	clinical testing	Variant summary: LAMB3 c.2914C>T (p.Arg972X) 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 2e-05 in 251406 control chromosomes. c.2914C>T has been reported in the literature in individuals affected with Herlitz Junctional Epidermolysis Bullosa. These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490897	SCV002795841	pathogenic	Amelogenesis imperfecta type 1A; Junctional epidermolysis bullosa gravis of Herlitz; Junctional epidermolysis bullosa, non-Herlitz type	2021-12-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338631	SCV004047569	pathogenic	Junctional epidermolysis bullosa gravis of Herlitz		criteria provided, single submitter	clinical testing	The stop-gained variant c.2914C>T p.Arg972Ter in the LAMB3 gene has been reported in the compound heterozygous and homozygous state in individuals affected with Epidermolysis bullosa Yoshida et al., 2014; Pfendner et al., 2003. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It has been submitted to ClinVar as Pathogenic. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338632	SCV004047890	pathogenic	Junctional epidermolysis bullosa, non-Herlitz type		criteria provided, single submitter	clinical testing	The c.2914C>T (p.Arg972Ter) stop gained variant in LAMB3 gene has been observed in individuals affected with junctional epidermolysis bullosa (Vahidnezhad et al., 2017). The p.Pro790GlnfsTer98 variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.2914C>T in LAMB3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The c.2914C>T variant is novel (not in any individuals) in 1000 Genomes. Loss-of-function variants in LAMB3 are known to be pathogenic (Varki et al., 2006). For these reasons, this variant has been classified as Pathogenic.