rs137852526

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001278116.2(L1CAM):c.719C>T(p.Pro240Leu) variant causes a missense change. 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 23)

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 3.91

Variant links:

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]

L1CAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain Ig-like C2-type 3 (size 88) in uniprot entity L1CAM_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001278116.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant X-153870475-G-A is Pathogenic according to our data. Variant chrX-153870475-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10001.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 link	c.719C>T	p.Pro240Leu	missense_variant	Exon 8 of 29	ENST00000370060.7	NP_001265045.1	P32004-1
L1CAM	NM_000425.5 link	c.719C>T	p.Pro240Leu	missense_variant	Exon 7 of 28		NP_000416.1	P32004-1
L1CAM	NM_024003.3 link	c.719C>T	p.Pro240Leu	missense_variant	Exon 7 of 27		NP_076493.1	P32004-2
L1CAM	NM_001143963.2 link	c.704C>T	p.Pro235Leu	missense_variant	Exon 6 of 26		NP_001137435.1	P32004-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
L1CAM	ENST00000370060.7 link	c.719C>T	p.Pro240Leu	missense_variant	Exon 8 of 29	5	NM_001278116.2	ENSP00000359077.1	P32004-1
L1CAM	ENST00000361699.8 link	c.719C>T	p.Pro240Leu	missense_variant	Exon 7 of 27	1		ENSP00000355380.4	P32004-2
L1CAM	ENST00000361981.7 link	c.704C>T	p.Pro235Leu	missense_variant	Exon 6 of 26	1		ENSP00000354712.3	P32004-3
L1CAM	ENST00000370055.5 link	c.704C>T	p.Pro235Leu	missense_variant	Exon 7 of 27	5		ENSP00000359072.1	P32004-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked complicated corpus callosum dysgenesis

Pathogenic:5

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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), MASA/CRASH syndrome (MIM#303350) and hydrocephalus due to aqueductal stenosis/with congenital idiopathic intestinal pseudoobstruction/with Hirschsprung disease (MIM#307000). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Both inter and intra-familial variability have been reported (PMID: 7562969, 16650080). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Immunoglobulin domain (DECIPHER). (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 at least five unrelated males with a variety of brain abnormalities namely syndromic hydrocephalus (PMID: 8929944), hypoplastic corpus callosum and mild generalized ventriculomegaly (PMID: 16650080) and cerebellar hypoplasia (PMID: 31474318). This variant has been identified and classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 0906 - Segregation evidence for this variant is inconclusive. It has been identified in two brothers with hypoplastic corpus callosum and mild generalized ventriculomegaly (PMID: 16650080). It was also reported to have segregated in 4 affected males across multiple generations in a single family; however, data was not shown (PMID: 8929944). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by quad analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 18, 2019

Dobyns Lab, Seattle Children's Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 04, 2019

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2022

Eurofins-Biomnis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked hydrocephalus syndrome

Pathogenic:2

May 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 27, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 8929944, 16650080] -

not provided

Pathogenic:2

Jul 11, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8929944, 31474318, 16650080, 25641508) -

Jan 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia

Pathogenic:1

Jan 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 240 of the L1CAM protein (p.Pro240Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of L1 syndrome (PMID: 8929944, 10797421, 16650080, 31474318). ClinVar contains an entry for this variant (Variation ID: 10001). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

L1 syndrome

Pathogenic:1

May 03, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: L1CAM c.719C>T (p.Pro240Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182408 control chromosomes. c.719C>T has been reported in the literature in four individuals affected with L1 Syndrome (example, Aldinger_2019, Basel-Vanagaite_2006, Gu_1996). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31474318, 16650080, 8929944). ClinVar contains an entry for this variant (Variation ID: 10001). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

MASA syndrome

Pathogenic:1

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital cerebellar hypoplasia

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

X-linked hydrocephalus syndrome;C0795953:MASA syndrome;C1839909:X-linked complicated corpus callosum dysgenesis

Pathogenic:1

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

.;D;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;.;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.6

.;M;.;M

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-9.2

D;D;D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0, 0.95

.;D;.;P

Vest4

0.78

MutPred

0.89

.;Gain of MoRF binding (P = 0.0405);.;Gain of MoRF binding (P = 0.0405);

MVP

0.93

MPC

1.5

ClinPred

1.0

GERP RS

4.8

Varity_R

0.99

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over