chrX-153867800-T-A

Variant names:

• chrX-153867800-T-A
• rs863224494
• NM_001278116.2:c.1939A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001278116.2(L1CAM):​c.1939A>T​(p.Lys647*) variant causes a stop gained, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: L1CAM NM_001278116.2 stop_gained, splice_region
• Scores: Splicing: ADA: 0.2357
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.40
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• L1 syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked hydrocephalus with stenosis of the aqueduct of Sylvius

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• MASA syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• X-linked complicated corpus callosum dysgenesis

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• X-linked complicated spastic paraplegia type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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-153867800-T-A is Pathogenic according to our data. Variant chrX-153867800-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 216069.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.1939A>T	p.Lys647*	stop_gained, splice_region_variant	Exon 16 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.1939A>T	p.Lys647*	stop_gained, splice_region_variant	Exon 15 of 28		NP_000416.1
L1CAM	NM_024003.3	c.1939A>T	p.Lys647*	stop_gained, splice_region_variant	Exon 15 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.1924A>T	p.Lys642*	stop_gained, splice_region_variant	Exon 14 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.1939A>T	p.Lys647*	stop_gained, splice_region_variant	Exon 16 of 29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Feb 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal at codon 647 (p.Lys647*). It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in L1CAM are known to be pathogenic (PMID: 11438988, 10797421). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		1.4
Vest4		0.77
GERP RS		3.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.24
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs863224494; hg19: chrX-153133255;