Submissions for variant NM_000228.3(LAMB3):c.877T>A (p.Cys293Ser)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002467160	SCV002762267	likely pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16473856, 9690563)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002467160	SCV003524066	pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 293 of the LAMB3 protein (p.Cys293Ser). This variant is present in population databases (rs759084687, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive junctional epidermolysis bullosa (PMID: 9690563, 11810295). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1803490). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LAMB3 protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403841	SCV004121840	likely pathogenic	Junctional epidermolysis bullosa	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: LAMB3 c.877T>A (p.Cys293Ser) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251428 control chromosomes. c.877T>A has been reported in the literature in as a compound heterozygous genotype in at-least two individuals affected with Junctional Epidermolysis Bullosa (example, Pulkkinen_1998, Robbins_2001 cited in Nakano_2002). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15538630, 11810295, 9690563, 11296269, 36246619). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.