rs137852520

Positions:

• chrX-153868866-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001278116.2(L1CAM):​c.1354G>A​(p.Gly452Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.34

Genes affected

L1CAM (HGNC:6470): (L1 cell adhesion molecule) The protein encoded by this gene is an axonal glycoprotein belonging to the immunoglobulin supergene family. The ectodomain, consisting of several immunoglobulin-like domains and fibronectin-like repeats (type III), is linked via a single transmembrane sequence to a conserved cytoplasmic domain. This cell adhesion molecule plays an important role in nervous system development, including neuronal migration and differentiation. Mutations in the gene cause X-linked neurological syndromes known as CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus). Alternative splicing of this gene results in multiple transcript variants, some of which include an alternate exon that is considered to be specific to neurons. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain Ig-like C2-type 5 (size 82) in uniprot entity L1CAM_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001278116.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-153868866-C-T is Pathogenic according to our data. Variant chrX-153868866-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.1354G>A	p.Gly452Arg	missense_variant	12/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.1354G>A	p.Gly452Arg	missense_variant	11/28		NP_000416.1
L1CAM	NM_024003.3	c.1354G>A	p.Gly452Arg	missense_variant	11/27		NP_076493.1
L1CAM	NM_001143963.2	c.1339G>A	p.Gly447Arg	missense_variant	10/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.1354G>A	p.Gly452Arg	missense_variant	12/29	5	NM_001278116.2	ENSP00000359077	A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked hydrocephalus syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1994	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 10, 2018

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). -

L1 syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 19, 2021

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. -

Hydrocephalus due to aqueductal stenosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	.;D;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.0	.;H;.;H
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.2	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.87
MutPred		0.93		.;Gain of solvent accessibility (P = 0.0097);.;Gain of solvent accessibility (P = 0.0097);
MVP		0.96
MPC		1.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852520; hg19: chrX-153134321; COSMIC: COSV62831100; COSMIC: COSV62831100;