Submissions for variant NM_000228.3(LAMB3):c.124C>T (p.Arg42Ter)

gnomAD frequency: 0.00006  dbSNP: rs80356680

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000261136	SCV000329389	pathogenic	not provided	2022-10-17	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: 30544381, 25525159, 8824879, 7706760, 9767254, 32484238, 31589614, 33274474)
Fulgent Genetics, Fulgent Genetics	RCV000762879	SCV000893259	pathogenic	Amelogenesis imperfecta type 1A; Junctional epidermolysis bullosa gravis of Herlitz; Junctional epidermolysis bullosa, non-Herlitz type	2018-10-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000015641	SCV001193875	pathogenic	Junctional epidermolysis bullosa gravis of Herlitz	2019-12-20	criteria provided, single submitter	clinical testing	NM_000228.2(LAMB3):c.124C>T(R42*) is classified as pathogenic in the context of LAMB3-related Herlitz junctional epidermolysis bullosa. Sources cited for classification include the following: PMID 11023379 and 8983017. Classification of NM_000228.2(LAMB3):c.124C>T(R42*) 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	RCV000261136	SCV001209373	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg42*) 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 (rs80356680, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with autosomal recessive junctional epidermolysis bullosa (PMID: 7706760, 8824879, 8983017, 30544381). ClinVar contains an entry for this variant (Variation ID: 14541). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193779	SCV001362889	pathogenic	Junctional epidermolysis bullosa, non-Herlitz type	2019-02-07	criteria provided, single submitter	clinical testing	Variant summary: The variant, LAMB3 c.124C>T (p.Arg42X) 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 (eg. c.1903C>T (p.Arg635X), c.1978C>T(p.Arg660X)). The variant allele was found at a frequency of 4.7e-05 in 277176 control chromosomes (gnomAD) and has been reported in the literature as a mutational hot spot in multiple individuals affected with Junctional Epidermolysis Bullosa (JEB), where some of these patients, including 2 homozygotes, were affected by the most severe, Herlitz type JEB (Kivirkko 1996, Matsui 1998, Hammersen 2016), while others had less severe forms of JEB (e.g. Abu Sa'd 2006, McGrath 1995). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact of the variant, and demonstrated strongly decreased mRNA levels, and lack of the protein product, in samples from a homozygous patient (Matsui 1998). Two clinical diagnostic laboratories have 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.
Revvity Omics, Revvity	RCV000261136	SCV003818988	pathogenic	not provided	2022-01-31	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001193779	SCV005400717	pathogenic	Junctional epidermolysis bullosa, non-Herlitz type	2023-06-22	criteria provided, single submitter	clinical testing	The observed stop gain c.124C>T(p.Arg42Ter) variant in LAMB3 gene has been reported in compound heterozygous state in multiple patients affected with epidermolysis bullosa (Nakano A, et. al.,2000; Hammersen J, et. al., 2016; Wang H, et. al., 2018). Experimental evidence shows an impact of the variant, and demonstrated strongly decreased mRNA levels, and lack of the protein product (Mellerio JE, et. al., 1998). This variant is present with an allele frequency of 0.006% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - disease causing) predict damaging effect on protein structure and function for this variant. The nucleotide change c.124C>T in LAMB3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in LAMB3 are known to be pathogenic (Nakano A, et. al., 2000). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000015641	SCV000035906	pathogenic	Junctional epidermolysis bullosa gravis of Herlitz	1998-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000015641	SCV000040564	not provided	Junctional epidermolysis bullosa gravis of Herlitz		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003904843	SCV004732398	pathogenic	LAMB3-related disorder	2024-03-02	no assertion criteria provided	clinical testing	The LAMB3 c.124C>T variant is predicted to result in premature protein termination (p.Arg42*). This variant has been reported in the homozygous and compound heterozygous states in association with autosomal recessive LAMB3-related disorders (Rossi et al. 2021. PubMed ID: 33274474; Kivirikko et al. 1996. PubMed ID: 8824879). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in LAMB3 are expected to be pathogenic. This variant is interpreted as pathogenic.