rs797044787

Variant names:

• chrX-153870123-G-A
• rs797044787
• NM_001278116.2:c.924C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001278116.2(L1CAM):​c.924C>T​(p.Gly308Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: L1CAM NM_001278116.2 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.246

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-153870123-G-A is Pathogenic according to our data. Variant chrX-153870123-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.924C>T	p.Gly308Gly	synonymous_variant	Exon 9 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.924C>T	p.Gly308Gly	synonymous_variant	Exon 8 of 28		NP_000416.1
L1CAM	NM_024003.3	c.924C>T	p.Gly308Gly	synonymous_variant	Exon 8 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.909C>T	p.Gly303Gly	synonymous_variant	Exon 7 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.924C>T	p.Gly308Gly	synonymous_variant	Exon 9 of 29	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361699.8	c.924C>T	p.Gly308Gly	synonymous_variant	Exon 8 of 27	1		ENSP00000355380.4
L1CAM	ENST00000361981.7	c.909C>T	p.Gly303Gly	synonymous_variant	Exon 7 of 26	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.909C>T	p.Gly303Gly	synonymous_variant	Exon 8 of 27	5		ENSP00000359072.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 02, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNA studies demonstrate a damaging effect: use of a cryptic splice donor site which led to the in-frame deletion of the last 23 amino acids of exon 8 and includes part of the critical Ig domain 3 (PMID: 9643285, 25641508); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21961551, 11170723, 14556828, 25436522, 9643285, 31572438, 10469653, 25039760, 25641508) -

Feb 10, 2015

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia Pathogenic:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 308 of the L1CAM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the L1CAM protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of L1 syndrome (PMID: 9643285, 25039760). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 198728). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

X-linked hydrocephalus syndrome Pathogenic:1

Jun 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

L1CAM-related disorder Pathogenic:1

Dec 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L1CAM c.924C>T variant is not predicted to result in an amino acid change (p.=). This variant was reported in multiple affected males with X-linked hydrocephalus from two families (Du et al 1998. PubMed ID: 9643285; Serikawa T et al 2014. PubMed ID: 25039760). RT-PCR analysis indicated that this variant generates a novel splice site within exon 8 and leads to aberrant splicing (Du et al. 1998. PubMed ID: 9643285). In addition, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044787; hg19: chrX-153135578; COSMIC: COSV100648896; COSMIC: COSV100648896;