ClinVar Genomic variation as it relates to human health

Variant summary: L1CAM c.551G>A (p.Arg184Gln) results in a conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183331 control chromosomes. c.551G>A has been reported in the literature in individuals affected with L1 Syndrome (hydrocephalus, e.g. Jouet_1994, Li_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (e.g. Moulding_2000, Kudumala_2013). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

This missense change has been observed in individuals with clinical features of L1CAM-related conditions (PMID: 9195224, 32416898, 34510796). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg184 amino acid residue in L1CAM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8826452, 10632110; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects L1CAM function (PMID: 20621658). 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 L1CAM protein function. ClinVar contains an entry for this variant (Variation ID: 9991). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 184 of the L1CAM protein (p.Arg184Gln).

The p.R184Q pathogenic mutation (also known as c.551G>A), located in coding exon 6 of the L1CAM gene, results from a G to A substitution at nucleotide position 551. The arginine at codon 184 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been described in numerous individuals with hydrocephalus or ventriculomegaly plus additional features including mental retardation, spastic paraplegia/shuffling gait, aphasia, and thumb deformities, with most individuals experiencing death within 1 year of birth (Moulding HD et al. J. Neurosci., 2000 Aug;20:5696-702; De Angelis E et al. EMBO J., 1999 Sep;18:4744-53). In addition, this mutation has been observed to result in impaired protein trafficking and ligand binding (Moulding HD et al. J. Neurosci., 2000 Aug;20:5696-702; Itoh K et al. J. Neurosci. Res., 2011 Oct;89:1637-45). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.