rs1557090161

Positions:

• chrX-153864698-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.3053C>G​(p.Ser1018Ter) 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: L1CAM NM_001278116.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.688

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-153864698-G-C is Pathogenic according to our data. Variant chrX-153864698-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 435689.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.3053C>G	p.Ser1018Ter	stop_gained	24/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3053C>G	p.Ser1018Ter	stop_gained	23/28		NP_000416.1
L1CAM	NM_024003.3	c.3053C>G	p.Ser1018Ter	stop_gained	23/27		NP_076493.1
L1CAM	NM_001143963.2	c.3038C>G	p.Ser1013Ter	stop_gained	22/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.3053C>G	p.Ser1018Ter	stop_gained	24/29	5	NM_001278116.2	ENSP00000359077	A1
L1CAM	ENST00000361699.8	c.3053C>G	p.Ser1018Ter	stop_gained	23/27	1		ENSP00000355380	P4
L1CAM	ENST00000361981.7	c.3038C>G	p.Ser1013Ter	stop_gained	22/26	1		ENSP00000354712	A1
L1CAM	ENST00000370055.5	c.3038C>G	p.Ser1013Ter	stop_gained	23/27	5		ENSP00000359072	A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

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

Mar 15, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1018*) in the L1CAM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in L1CAM are known to be pathogenic (PMID: 19846429). This variant has not been reported in the literature in individuals affected with L1CAM-related conditions. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 435689). -

Hydrocephalus due to aqueductal stenosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Benign	0.90
FATHMM_MKL	Benign	0.082	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.75
GERP RS		-2.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1557090161; hg19: chrX-153130153;