rs879253717

Positions:

• chrX-153864893-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001278116.2(L1CAM):​c.2974C>T​(p.Gln992Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: L1CAM NM_001278116.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.62

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153864893-G-A is Pathogenic according to our data. Variant chrX-153864893-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10000.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.2974C>T	p.Gln992Ter	stop_gained	23/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.2974C>T	p.Gln992Ter	stop_gained	22/28		NP_000416.1
L1CAM	NM_024003.3	c.2974C>T	p.Gln992Ter	stop_gained	22/27		NP_076493.1
L1CAM	NM_001143963.2	c.2959C>T	p.Gln987Ter	stop_gained	21/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.2974C>T	p.Gln992Ter	stop_gained	23/29	5	NM_001278116.2	ENSP00000359077	A1
L1CAM	ENST00000361699.8	c.2974C>T	p.Gln992Ter	stop_gained	22/27	1		ENSP00000355380	P4
L1CAM	ENST00000361981.7	c.2959C>T	p.Gln987Ter	stop_gained	21/26	1		ENSP00000354712	A1
L1CAM	ENST00000370055.5	c.2959C>T	p.Gln987Ter	stop_gained	22/27	5		ENSP00000359072	A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hydrocephalus, X-linked, with congenital idiopathic intestinal pseudoobstruction Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 2004

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2017

The Q992X nonsense variant in the L1CAM gene has been reported previously in a patient with X-linked hydrocephalus (Okamoto et al., 2004). Of note, that patient also had Hirschsprung disease, which has been reported in the literature in several other patients with X-linked hydrocephalus and L1CAM variants (Parisi et al., 2002). The Q992X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.66	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.87
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs879253717; hg19: chrX-153130348;