ClinVar Genomic variation as it relates to human health

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 309 of the L1CAM protein (p.Glu309Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with L1CAM-related conditions (PMID: 7762552, 9300653, 25666757; Invitae). This variant is also known as E304K. ClinVar contains an entry for this variant (Variation ID: 838485). 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 not expected to disrupt L1CAM protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects L1CAM function (PMID: 10469653, 11772994, 15555929, 19617634, 22973895). 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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with partial agenesis of corpus callosum (MIM#304100), MASA/CRASH syndrome (MIM#303350) and hydrocephalus due to aqueductal stenosis/with congenital idiopathic intestinal pseudoobstruction/with Hirschsprung disease (MIM#307000). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Both interfamilial and intrafamilial variability have been reported (PMID: 7562969, 16650080). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for an X-linked recessive condition (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated immunoglobulin 3 domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by clinical laboratories in ClinVar and observed in multiple individuals with progressive hydrocephalus, enlarged ventricles, intellectual disability, spastic paraplegia, aphasia and adducted thumbs, or CRASH syndrome (PMIDs: 25666757, 7762552, 9300653). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. This variant has been shown to decrease cell surface expression, decrease cell adhesion and result in the production of fewer and shorter neurites (PMID: 22973895). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The observed missense variant c.925G>A (p.Glu309Lys) in L1CAM gene has been reported previously in hemizygous state in individuals affected with L1CAM related condition (Kudumala S et al. 2013). Functional studies have shown the variant to impair protein cell-surface expression and ligand binding (Tagliavacca et al. 2013). The p.Glu309Lys variant has allele frequency 0.0005% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic/Likely Pathogenic (multiple submiters). Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Tolerated and Mutation Taster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Glu309Lys in L1CAM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 309 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate a damaging effect, as this variant led to decreased cell-matrix adhesion, decreased cell migration, loss of axon guidance, and loss of proper synapse formation (Tagliavacca et al., 2013); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 15555929, 9610803, 11438988, 24155914, 22973895, 11772994, 16760466, 7920660, 7762552)

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000005, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000838485, PS1_S). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: L1CAM c.925G>A (p.Glu309Lys) results in a conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183141 control chromosomes (i.e., 1 heterozygous female; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.925G>A has been reported in the literature in multiple hemizygous males affected with L1 Syndrome (Jouet_1995, McMichael_2015, Fransen_1997, Mir_2023 (preprint, no PMID)), and the variant has been shown to segregate with disease in related individuals from multiple independent families. These data indicate that the variant is very likely to be associated with disease. Functional studies have shown the variant impairs protein cell-surface expression and ligand binding (eg. Nagaraj_2009, Tagliavacca_2013). The following publications have been ascertained in the context of this evaluation (PMID: 9300653, 7762552, 25666757, 19617634, 22973895). Four submitters have reported 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 pathogenic.