rs137852518

Variant names:

• chrX-153870403-C-A
• rs137852518
• NM_001278116.2:c.791G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-153870403-C-A
• chrX-153870403-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001278116.2(L1CAM):​c.791G>T​(p.Cys264Phe) variant causes a missense change involving the alteration of a non-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. C264Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.08
• Publications: 0 publications found

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]

L1CAM Gene-Disease associations (from GenCC):

• L1 syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked hydrocephalus with stenosis of the aqueduct of Sylvius

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• MASA syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• X-linked complicated corpus callosum dysgenesis

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• X-linked complicated spastic paraplegia type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153870403-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9986.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-153870403-C-A is Pathogenic according to our data. Variant chrX-153870403-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1379028.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.791G>T	p.Cys264Phe	missense_variant	Exon 8 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.791G>T	p.Cys264Phe	missense_variant	Exon 7 of 28		NP_000416.1
L1CAM	NM_024003.3	c.791G>T	p.Cys264Phe	missense_variant	Exon 7 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.776G>T	p.Cys259Phe	missense_variant	Exon 6 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.791G>T	p.Cys264Phe	missense_variant	Exon 8 of 29	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361699.8	c.791G>T	p.Cys264Phe	missense_variant	Exon 7 of 27	1		ENSP00000355380.4
L1CAM	ENST00000361981.7	c.776G>T	p.Cys259Phe	missense_variant	Exon 6 of 26	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.776G>T	p.Cys259Phe	missense_variant	Exon 7 of 27	5		ENSP00000359072.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Aug 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the p.Cys264 amino acid residue in L1CAM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8401576, 12514225). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of L1CAM-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces cysteine with phenylalanine at codon 264 of the L1CAM protein (p.Cys264Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	.;D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	.;H;.;H
PhyloP100		3.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-11	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.87
MutPred		0.95		.;Gain of sheet (P = 0.1539);.;Gain of sheet (P = 0.1539);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137852518; hg19: chrX-153135858;