rs137852522

Positions:

• chrX-153862856-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001278116.2(L1CAM):​c.3581C>T​(p.Ser1194Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,854 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.73

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 14 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity L1CAM_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant X-153862856-G-A is Pathogenic according to our data. Variant chrX-153862856-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9993.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.3581C>T	p.Ser1194Leu	missense_variant	29/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3581C>T	p.Ser1194Leu	missense_variant	28/28		NP_000416.1
L1CAM	NM_024003.3	c.3569C>T	p.Ser1190Leu	missense_variant	27/27		NP_076493.1
L1CAM	NM_001143963.2	c.3554C>T	p.Ser1185Leu	missense_variant	26/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.3581C>T	p.Ser1194Leu	missense_variant	29/29	5	NM_001278116.2	ENSP00000359077	A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097854 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363230

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked hydrocephalus syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics Institute, Tel Aviv Sourasky Medical Center	May 12, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1994	- -

MASA syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1994

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2015

The p.S1194L variant (also known as c.3581C>T) is located in exon 28 of the L1CAM gene. This alteration results from a C to T substitution at nucleotide position 3581. The serine at codon 1194 is replaced by leucine, an amino acid with dissimilar properties. In one published study, this variant was observed to segregate with disease in two maternally related male probands diagnosed with MASA syndrome and two obligate carrier females and was absent in two unaffected maternally related males. An additional affected male in this family was diagnosed with congenital hydrocephalus, extreme macrocephaly, severe spasticity, and MR (HSAS) but died at age 15 years and was untested in this family study (Fransen, E et al. Hum Mol Genet 1994;3:2255-2256). This variant has been observed in a male proband tested by our laboratory diagnosed with macrocephaly, agenesis of the corpus collosum, and periventricular volume loss on MRI and whose family history consististed of two maternally related males in separate generations diagnosed with hydrocephalus and mental retardation respectively. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, its clinical significance remains unclear. -

Hydrops fetalis;C3278123:Severe hydrocephalus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Reproductive Medicine, Peking University Third Hospital

Oct 16, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2022

Published functional studies demonstrate a damaging effect due to reduction of neuronal migration and MAP kinase activation (Thelen et al., 2002); 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: 11438988, 10908608, 11222639, 28152038, 7881431, 30197081, 31680349, 12077189) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;D;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;.;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.5	.;M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;.;D
Vest4		0.61
MutPred		0.75		.;Gain of catalytic residue at S1194 (P = 0.009);.;.;.;
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.59
gMVP		0.90

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: rs137852522; hg19: chrX-153128311;