rs137852524

chrX-153869818-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001278116.2(L1CAM):c.1108G>A(p.Gly370Arg) 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: 23)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.24

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-153869818-C-T is Pathogenic according to our data. Variant chrX-153869818-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.1108G>A	p.Gly370Arg	missense_variant	10/29	ENST00000370060.7
L1CAM	NM_000425.5	c.1108G>A	p.Gly370Arg	missense_variant	9/28
L1CAM	NM_024003.3	c.1108G>A	p.Gly370Arg	missense_variant	9/27
L1CAM	NM_001143963.2	c.1093G>A	p.Gly365Arg	missense_variant	8/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.1108G>A	p.Gly370Arg	missense_variant	10/29	5	NM_001278116.2	A1
L1CAM	ENST00000361699.8	c.1108G>A	p.Gly370Arg	missense_variant	9/27	1		P4
L1CAM	ENST00000361981.7	c.1093G>A	p.Gly365Arg	missense_variant	8/26	1		A1
L1CAM	ENST00000370055.5	c.1093G>A	p.Gly365Arg	missense_variant	9/27	5		A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2019

This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 370 of the L1CAM protein (p.Gly370Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant has been observed to segregate with L1 syndrome in a family (PMID: 7562969,8062435). ClinVar contains an entry for this variant (Variation ID: 9995). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect L1CAM protein function (PMID: 11772994). -

MASA syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1995

- -

X-linked hydrocephalus syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. This variant was detected in hemizygous state. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2020

Published functional studies demonstrate that G370R affects a key residue in the Ig4 domain and significantly reduces homophilic ligand binding (De Angelis et al., 2002); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11772994, 7562969, 8062435) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Uncertain	25
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.8	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.88
MutPred		0.98		.;Gain of MoRF binding (P = 0.0162);.;Gain of MoRF binding (P = 0.0162);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.98

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: rs137852524; hg19: chrX-153135273;