rs137852525

Positions:

• chrX-153866826-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001278116.2(L1CAM):​c.2254G>A​(p.Val752Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,097,920 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.16

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 16 ACMG points.

• PM1: In a domain Fibronectin type-III 2 (size 93) in uniprot entity L1CAM_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001278116.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-153866826-C-T is Pathogenic according to our data. Variant chrX-153866826-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9998.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.2254G>A	p.Val752Met	missense_variant	19/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.2254G>A	p.Val752Met	missense_variant	18/28		NP_000416.1
L1CAM	NM_024003.3	c.2254G>A	p.Val752Met	missense_variant	18/27		NP_076493.1
L1CAM	NM_001143963.2	c.2239G>A	p.Val747Met	missense_variant	17/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.2254G>A	p.Val752Met	missense_variant	19/29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000549 AC: 1 AN: 182191 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66961

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097920 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363330

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked hydrocephalus syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 08, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with partial agenesis of corpus callosum (MIM#304100), congenital hydrocephalus (MIM#307000), and MASA syndrome (MIM#303350). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Both interfamilial and intrafamilial variability have been reported (PMID: 7562969,16650080). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated fibronectin type III domain (DECIPHER; PMID: 11772994). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple hemizygous male individuals with hydrocephalus (PMID: 11857550, 9268105, 17328266, 35088901). Additionally, it has been reported as pathogenic by a clinical laboratory (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. It has been shown to reduce homophilic L1 binding and TAX-1 binding, as well as having reduced cell surface expression, relative to wild-type protein (PMID: 11772994). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2002	- -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 24, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects L1CAM function (PMID: 11772994). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on L1CAM protein function. ClinVar contains an entry for this variant (Variation ID: 9998). This missense change has been observed in individual(s) with L1CAM-related conditions (PMID: 9268105, 11857550, 17328266, 19953645, 23820807). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 752 of the L1CAM protein (p.Val752Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2024

Published functional studies demonstrate a damaging effect including reduced homophilic binding and reduced binding to TAX-1 (PMID: 11772994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35088901, 10767310, 19846429, 36307859, 33768880, 37453721, Ahmed2023[casereport], 25641508, 9268105, 11857550, 11772994, 17328266) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	.;D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.3	.;M;.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.73
MutPred		0.91		.;Gain of catalytic residue at V748 (P = 0.0473);.;Gain of catalytic residue at V748 (P = 0.0473);
MVP		0.96
MPC		1.5
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.97

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: rs137852525; hg19: chrX-153132281; COSMIC: COSV62830040; COSMIC: COSV62830040;