Submissions for variant NM_001278116.2(L1CAM):c.925G>A (p.Glu309Lys)

gnomAD frequency: 0.00001  dbSNP: rs367665974

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001040041	SCV001203596	likely pathogenic	Spastic paraplegia	2023-12-20	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV001266763	SCV001444940	likely pathogenic	Inborn genetic diseases	2018-12-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001545171	SCV001764448	pathogenic	not provided	2023-06-05	criteria provided, single submitter	clinical testing	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)
3billion	RCV001809962	SCV002058977	likely pathogenic	X-linked complicated corpus callosum dysgenesis	2022-01-03	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002239304	SCV002511498	pathogenic	L1 syndrome	2023-08-10	criteria provided, single submitter	clinical testing	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.