rs137852524
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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
NM_001278116.2 missense
Scores
12
2
1
Clinical Significance
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
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
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 | - - |
L1CAM-related disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 17, 2023 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
1.0
.;D;.;D
Vest4
MutPred
0.98
.;Gain of MoRF binding (P = 0.0162);.;Gain of MoRF binding (P = 0.0162);
MVP
MPC
1.6
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at