Submissions for variant NM_000228.3(LAMB3):c.31dup (p.Leu11fs)

dbSNP: rs777672897

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781492	SCV000919569	pathogenic	Junctional epidermolysis bullosa gravis of Herlitz	2018-07-05	criteria provided, single submitter	clinical testing	Variant summary: LAMB3 c.31dupC (p.Leu11ProfsX43) 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.1365_1366delCA, p.Asn456fsX7; c.1903C>T, p.Arg635X). The variant allele was found at a frequency of 2.9e-05 in 243276 control chromosomes (gnomAD). The variant, c.31dupC, has been reported in the literature in multiple individuals affected with Junctional Epidermolysis Bullosa in compound heterozygosity with other known pathogenic variants (Herlitz and non-Herlitz) (Pulkkinen_1995, Yuen_2011, Muhle_2005, Posteraro_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792432	SCV000931730	pathogenic	not provided	2024-02-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu11Profs*43) 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 (rs777672897, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Herlitz and non-Herlitz junctional epidermolysis bullosa (PMID: 8824879, 15373767, 21801158). This variant is also known as 29insC and 31insC. ClinVar contains an entry for this variant (Variation ID: 633285). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000792432	SCV001168539	pathogenic	not provided	2025-01-21	criteria provided, single submitter	clinical testing	Frameshift 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: 7550237, 8824879, 21801158, 16473856, 15538630, 15373767, 34426522, 33274474, 17916201)
CeGaT Center for Human Genetics Tuebingen	RCV000792432	SCV002062871	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002245666	SCV002512761	pathogenic	Junctional epidermolysis bullosa, non-Herlitz type	2021-10-26	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PM2 moderate, PM3 very strong
Fulgent Genetics, Fulgent Genetics	RCV002493427	SCV002789662	pathogenic	Amelogenesis imperfecta type 1A; Junctional epidermolysis bullosa gravis of Herlitz; Junctional epidermolysis bullosa, non-Herlitz type	2021-08-23	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000781492	SCV005051848	pathogenic	Junctional epidermolysis bullosa gravis of Herlitz	2024-02-01	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003928269	SCV004742576	pathogenic	LAMB3-related disorder	2024-03-02	no assertion criteria provided	clinical testing	The LAMB3 c.31dupC variant is predicted to result in a frameshift and premature protein termination (p.Leu11Profs*43). This variant has been reported in the homozygous and compound heterozygous states in patients with autosomal recessive LAMB3-related disorders (Yuen et al. 2011. PubMed ID: 21801158; Rossi et al. 2021. PubMed ID: 33274474; Pulkkinen et al. 1995. PubMed ID: 7550237). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in LAMB3 are expected to be pathogenic. This variant is interpreted as pathogenic.