Submissions for variant NM_001278116.2(L1CAM):c.1354G>A (p.Gly452Arg)

dbSNP: rs137852520

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254986	SCV000321854	pathogenic	not provided	2017-10-16	criteria provided, single submitter	clinical testing	The G452R missense variant in the L1CAM gene has been reported previously in association with X-linked hydrocephalus (Jouet et al., 1994). The variant is not observed in large population cohorts (Lek et al., 2016). The G452R variant is a non-conservative amino acid substitution within the Ig5 domain of the protein's extracellular region, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies show that G452R at this key residue reduces ligand binding strength (De Angelis et al., 1999; Kenwrick et al., 2000; De Angelis et al., 2002). We interpret this variant as pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000503947	SCV000595481	pathogenic	Hydrocephalus due to aqueductal stenosis	2016-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000685761	SCV000813258	pathogenic	Spastic paraplegia	2018-04-10	criteria provided, single submitter	clinical testing	This variant has been reported to segregate with X-linked hydrocephalus in a family (PMID: 7920659). ClinVar contains an entry for this variant (Variation ID: 9990). Experimental studies have shown that this missense change results in reduced ligand binding, reduced cell surface expression, and abnormal cellular protein retention (PMID: 11772994, 10469653). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine with arginine at codon 452 of the L1CAM protein (p.Gly452Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553633	SCV001774566	pathogenic	L1 syndrome	2021-07-19	criteria provided, single submitter	clinical testing	Variant summary: L1CAM c.1354G>A (p.Gly452Arg) results in a non-conservative amino acid change located in one of the immunoglobulin-like domains (IPR007110) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183404 control chromosomes (gnomAD). The variant, c.1354G>A, has been reported in the literature in individuals affected with L1 Syndrome, and was reported to co-segregate with the disease in a family (Jouet_1994, Gregory_2019, Li_2020). These data indicate that the variant likely associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in reduced cell surface expression, and strongly decreases both homophilic- and heterophilic ligand interactions (DeAngelis_1999, DeAngelis_2002). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000010671	SCV000030897	pathogenic	X-linked hydrocephalus syndrome	1994-07-01	no assertion criteria provided	literature only
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000010671	SCV003927855	pathogenic	X-linked hydrocephalus syndrome	2023-04-01	no assertion criteria provided	clinical testing