Submissions for variant NM_002291.3(LAMB1):c.4188+1G>C

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003104499	SCV003780965	likely pathogenic	not provided	2024-04-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 27 of the LAMB1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LAMB1 are known to be pathogenic (PMID: 23472759, 25925986). This variant is present in population databases (rs142670565, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with LAMB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2413703). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003226000	SCV003922125	pathogenic	Cobblestone lissencephaly without muscular or ocular involvement	2023-05-02	criteria provided, single submitter	curation	The heterozygous c.4188+1G>C variant in LAMB1 was identified by our study, in the compound heterozygous state, along with a likely pathogenic variant (ClinVar Variation ID: 981899), in one individual with epilepsy and intellectual disability. Trio genome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 981899). The c.4188+1G>C variant in LAMB1 has not been previously reported in individuals with cobblestone lissencephaly without muscular or ocular involvement but has been identified in 0.005% (3/65480) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs142670565). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. RNAseq performed on affected tissue (from the individual identified by our study) showed alternate splicing of exon 27. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function is an established disease mechanism of autosomal recessive cobblestone lissencephaly without muscular or ocular involvement. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cobblestone lissencephaly without muscular or ocular involvement. ACMG/AMP Criteria applied: PVS1, PS3_Moderate, PM2_Supporting (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV004750347	SCV005366717	likely pathogenic	LAMB1-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The LAMB1 c.4188+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. It is documented in just one allele in gnomAD (of ~250,000), indicating it is rare. In ClinVar, this variant is classified as pathogenic and likely pathogenic; one institution cites evidence of it being detected compound heterozygous in an affected individual (Variation ID: 2413703). Chain-terminating variants, such as those that disrupt splicing, have been shown to cause LAMB1-related disease (Järvelä. 2021. PubMed ID: 33710394; Okazaki et al. 2018. PubMed ID: 29888467). This variant is interpreted as likely pathogenic.