chrX-153868866-C-T

Variant names:

• chrX-153868866-C-T
• rs137852520
• NM_001278116.2:c.1354G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000321854: Functional studies show that G452R at this key residue reduces ligand binding strength (De Angelis et al., 1999" and additional evidence is available in ClinVar.

• 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
• Publications: 11 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: G2P, Orphanet, Genomics England PanelApp
• 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000321854: 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).; SCV000813258: 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).; SCV001774566: 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).
• 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 VariationId is 9990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	NM_001278116.2	MANE Select	c.1354G>A	p.Gly452Arg	missense	Exon 12 of 29	NP_001265045.1	P32004-1
	L1CAM	NM_000425.5		c.1354G>A	p.Gly452Arg	missense	Exon 11 of 28	NP_000416.1	P32004-1
	L1CAM	NM_024003.3		c.1354G>A	p.Gly452Arg	missense	Exon 11 of 27	NP_076493.1	P32004-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	ENST00000370060.7	TSL:5 MANE Select	c.1354G>A	p.Gly452Arg	missense	Exon 12 of 29	ENSP00000359077.1	P32004-1
	L1CAM	ENST00000361699.8	TSL:1	c.1354G>A	p.Gly452Arg	missense	Exon 11 of 27	ENSP00000355380.4	P32004-2
	L1CAM	ENST00000361981.7	TSL:1	c.1339G>A	p.Gly447Arg	missense	Exon 10 of 26	ENSP00000354712.3	P32004-3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	X-linked hydrocephalus syndrome (3)
1	-	-	L1 syndrome (1)
1	-	-	not provided (1)
1	-	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.93		Gain of solvent accessibility (P = 0.0097)
MVP		0.96
MPC		1.6
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.0084	Neutral
Varity_R		0.96
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

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