ClinVar Miner

Submissions for variant NM_001278116.2(L1CAM):c.1267+1G>A

dbSNP: rs1557092247
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522273 SCV000616760 likely pathogenic not provided 2024-05-14 criteria provided, single submitter clinical testing Reported in two individuals with L1CAM-related disorders (Fransen et al., 1996); Not observed in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame deletion of a critical region, the Ig domain 4 (Itoh et al, 2015).; This variant is associated with the following publications: (PMID: 8826452, 9450886, 9300653, 25525159, 12725590, 25641508, 23820807)
Labcorp Genetics (formerly Invitae), Labcorp RCV001221488 SCV001393536 pathogenic Spastic paraplegia 2019-10-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in L1CAM are known to be pathogenic (PMID: 19846429). This variant has been observed in individuals affected with L1CAM-related conditions (PMID: 8826452, 12725590). ClinVar contains an entry for this variant (Variation ID: 449047). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 10 of the L1CAM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260406 SCV001437383 pathogenic L1 syndrome 2020-09-03 criteria provided, single submitter clinical testing Variant summary: L1CAM c.1267+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 179457 control chromosomes (gnomAD). c.1267+1G>A has been reported in the literature in individuals affected with L1 Syndrome (example: Fransen_1996, Fransen_1998, Adle-Biassette_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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