rs875989884

Positions:

• chrX-153866700-G-A
• chrX-153866700-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001278116.2(L1CAM):​c.2380C>T​(p.Gln794Ter) variant causes a stop gained 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: L1CAM NM_001278116.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.0640

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153866700-G-A is Pathogenic according to our data. Variant chrX-153866700-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226120.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.2380C>T	p.Gln794Ter	stop_gained	19/29	ENST00000370060.7
L1CAM	NM_000425.5	c.2380C>T	p.Gln794Ter	stop_gained	18/28
L1CAM	NM_024003.3	c.2380C>T	p.Gln794Ter	stop_gained	18/27
L1CAM	NM_001143963.2	c.2365C>T	p.Gln789Ter	stop_gained	17/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.2380C>T	p.Gln794Ter	stop_gained	19/29	5	NM_001278116.2	A1
L1CAM	ENST00000361699.8	c.2380C>T	p.Gln794Ter	stop_gained	18/27	1		P4
L1CAM	ENST00000361981.7	c.2365C>T	p.Gln789Ter	stop_gained	17/26	1		A1
L1CAM	ENST00000370055.5	c.2365C>T	p.Gln789Ter	stop_gained	18/27	5		A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

L1 syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 07, 2022

Variant summary: L1CAM c.2380C>T (p.Gln794X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183249 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2380C>T in individuals affected with L1 Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

X-linked hydrocephalus syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Apr 05, 2016

The L1CAM pathogenic mutation was observed in a patient with hydrocephalus due to aqueductal stenosis. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.15	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.91
GERP RS		4.3

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: rs875989884; hg19: chrX-153132155;