Submissions for variant NM_000228.3(LAMB3):c.1439C>T (p.Pro480Leu)

gnomAD frequency: 0.00363  dbSNP: rs61734494

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000276955	SCV000353633	benign	Junctional epidermolysis bullosa	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000955278	SCV001101975	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251314	SCV001426861	benign	not specified	2022-11-17	criteria provided, single submitter	clinical testing	Variant summary: LAMB3 c.1439C>T (p.Pro480Leu) results in a non-conservative amino acid change located in the Laminin EGF domain (IPR002049) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 250774 control chromosomes, predominantly at a frequency of 0.01 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4- fold the estimated maximal expected allele frequency for a pathogenic variant in LAMB3 causing Junctional Epidermolysis Bullosa phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1439C>T has been reported in the literature in at least one individual affected with Epidermolysis Bullosa Simplex, however this patient had a co-occurring pathogenic variant in KRT14 (c.373C>T, p.R125C; classified pathogenic in ClinVar) that was cited as likely contributing to the patient's phenotype. This report does not provide unequivocal conclusions about association of the variant with Junctional Epidermolysis Bullosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000955278	SCV004125523	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	LAMB3: BP4, BS2