X-153869600-G-A

Variant names:

• chrX-153869600-G-A
• rs781830365
• NM_001278116.2:c.1187C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001278116.2(L1CAM):​c.1187C>T​(p.Pro396Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P396H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17204079).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	NM_001278116.2	MANE Select	c.1187C>T	p.Pro396Leu	missense	Exon 11 of 29	NP_001265045.1
	L1CAM	NM_000425.5		c.1187C>T	p.Pro396Leu	missense	Exon 10 of 28	NP_000416.1
	L1CAM	NM_024003.3		c.1187C>T	p.Pro396Leu	missense	Exon 10 of 27	NP_076493.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	ENST00000370060.7	TSL:5 MANE Select	c.1187C>T	p.Pro396Leu	missense	Exon 11 of 29	ENSP00000359077.1
	L1CAM	ENST00000361699.8	TSL:1	c.1187C>T	p.Pro396Leu	missense	Exon 10 of 27	ENSP00000355380.4
	L1CAM	ENST00000361981.7	TSL:1	c.1172C>T	p.Pro391Leu	missense	Exon 9 of 26	ENSP00000354712.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

L1CAM-related disorder Uncertain:1

Sep 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L1CAM c.1187C>T variant is predicted to result in the amino acid substitution p.Pro396Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.14	N
PhyloP100		1.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.20
Sift	Benign	0.26	T
Sift4G	Benign	0.52	T
Polyphen		0.018	B
Vest4		0.25
MutPred		0.51		Loss of disorder (P = 0.0682)
MVP		0.70
MPC		1.3
ClinPred		0.39	T
GERP RS		4.7
Varity_R		0.13
gMVP		0.93
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs781830365; hg19: chrX-153135055;