rs886039405

Positions:

• chrX-153870246-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001278116.2(L1CAM):​c.807-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,836 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: L1CAM NM_001278116.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.85

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-153870246-C-T is Pathogenic according to our data. Variant chrX-153870246-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265221.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.807-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.807-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_000416.1
L1CAM	NM_001143963.2	c.792-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001137435.1
L1CAM	NM_024003.3	c.807-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_076493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.807-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001278116.2	ENSP00000359077	A1
L1CAM	ENST00000361699.8	c.807-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000355380	P4
L1CAM	ENST00000361981.7	c.792-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000354712	A1
L1CAM	ENST00000370055.5	c.792-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000359072	A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095836 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 361354

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2016	The c.807-6 G>A splice site variant in the L1CAM gene has been previously reported in association with L1CAM-related disorders (MacFarlane et al., 1997; Du et al., 1998; Adle-Biassette et al., 2013). This pathogenic variant creates a new splice acceptor site upstream of the natural splice acceptor site in intron 7, and causes abnormal gene splicing leading to a premature stop codon (MacFarlane et al., 1997). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 10, 2017	- -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 25, 2022

This sequence change falls in intron 7 of the L1CAM gene. It does not directly 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 individuals with X-linked L1 syndrome (PMID: 9195224, 9521424, 19953645, 23820807). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265221). Studies have shown that this variant results in activation of a cryptic acceptor splice site and introduces a premature termination codon (PMID: 9195224). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

L1 syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 12, 2021

Variant summary: L1CAM c.807-6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3` acceptor site. Three predict the variant weakens a canonical 3` acceptor site. One predicts the variant abolishes a canonical 3` acceptor site. At least one publication reports experimental evidence that this variant results in causing aberrant splicing by creating a novel intron acceptor site (MacFarlane_1997, protein changed and predicted as p.Phe269LeufsX39 in L1CAM Mutation Database). The variant was absent in 182129 control chromosomes (gnomAD and publication data). c.807-6G>A has been reported in the literature in individuals affected with X-linked hydrocephalus and MASA syndrome (Du_1998, MacFarlane_1997, Nunes_2009). These data indicate that the variant is likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	22
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: -2
DS_AL_spliceai		0.39		Position offset: -6

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039405; hg19: chrX-153135701;