rs797044787

Positions:

• chrX-153870123-G-A

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.Gly308=) 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: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.924C>T	p.Gly308=	synonymous_variant	9/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.924C>T	p.Gly308=	synonymous_variant	8/28		NP_000416.1
L1CAM	NM_024003.3	c.924C>T	p.Gly308=	synonymous_variant	8/27		NP_076493.1
L1CAM	NM_001143963.2	c.909C>T	p.Gly303=	synonymous_variant	7/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.924C>T	p.Gly308=	synonymous_variant	9/29	5	NM_001278116.2	ENSP00000359077	A1
L1CAM	ENST00000361699.8	c.924C>T	p.Gly308=	synonymous_variant	8/27	1		ENSP00000355380	P4
L1CAM	ENST00000361981.7	c.909C>T	p.Gly303=	synonymous_variant	7/26	1		ENSP00000354712	A1
L1CAM	ENST00000370055.5	c.909C>T	p.Gly303=	synonymous_variant	8/27	5		ENSP00000359072	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2020	Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9643285, 10469653, 31572438, 25039760, 21961551, 11170723, 14556828, 25436522) -

X-linked hydrocephalus syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1998

- -

L1CAM-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2022

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;