rs137852521

Positions:

• chrX-153870933-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001278116.2(L1CAM):​c.551G>A​(p.Arg184Gln) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R184G) has been classified as Likely 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: 7.80

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 18 ACMG points.

• PM1: In a disulfide_bond (size 51) in uniprot entity L1CAM_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001278116.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant X-153870933-C-T is Pathogenic according to our data. Variant chrX-153870933-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9991.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.551G>A	p.Arg184Gln	missense_variant	7/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.551G>A	p.Arg184Gln	missense_variant	6/28		NP_000416.1
L1CAM	NM_024003.3	c.551G>A	p.Arg184Gln	missense_variant	6/27		NP_076493.1
L1CAM	NM_001143963.2	c.536G>A	p.Arg179Gln	missense_variant	5/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.551G>A	p.Arg184Gln	missense_variant	7/29	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361699.8	c.551G>A	p.Arg184Gln	missense_variant	6/27	1		ENSP00000355380.4
L1CAM	ENST00000361981.7	c.536G>A	p.Arg179Gln	missense_variant	5/26	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.536G>A	p.Arg179Gln	missense_variant	6/27	5		ENSP00000359072.1

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 05, 2023

This missense change has been observed in individuals with clinical features of L1CAM-related conditions (PMID: 9195224, 32416898, 34510796). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg184 amino acid residue in L1CAM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8826452, 10632110; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects L1CAM function (PMID: 20621658). 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 expected to disrupt L1CAM protein function. ClinVar contains an entry for this variant (Variation ID: 9991). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 184 of the L1CAM protein (p.Arg184Gln). -

L1 syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 20, 2022

Variant summary: L1CAM c.551G>A (p.Arg184Gln) results in a conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183331 control chromosomes. c.551G>A has been reported in the literature in individuals affected with L1 Syndrome (hydrocephalus, e.g. Jouet_1994, Li_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (e.g. Moulding_2000, Kudumala_2013). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2020

The p.R184Q pathogenic mutation (also known as c.551G>A), located in coding exon 6 of the L1CAM gene, results from a G to A substitution at nucleotide position 551. The arginine at codon 184 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been described in numerous individuals with hydrocephalus or ventriculomegaly plus additional features including mental retardation, spastic paraplegia/shuffling gait, aphasia, and thumb deformities, with most individuals experiencing death within 1 year of birth (Moulding HD et al. J. Neurosci., 2000 Aug;20:5696-702; De Angelis E et al. EMBO J., 1999 Sep;18:4744-53). In addition, this mutation has been observed to result in impaired protein trafficking and ligand binding (Moulding HD et al. J. Neurosci., 2000 Aug;20:5696-702; Itoh K et al. J. Neurosci. Res., 2011 Oct;89:1637-45). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

X-linked hydrocephalus syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	.;D;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.6	.;H;.;H
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.60
MutPred		0.96		.;Gain of methylation at K180 (P = 0.0533);.;Gain of methylation at K180 (P = 0.0533);
MVP		0.96
MPC		1.6
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.80
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137852521; hg19: chrX-153136388;