chrX-153868067-C-T

Variant names:

• chrX-153868067-C-T
• rs199888009
• NM_001278116.2:c.1759G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001278116.2(L1CAM):​c.1759G>A​(p.Gly587Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,749 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. G587R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09
• Publications: 6 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

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.1759G>A	p.Gly587Ser	missense	Exon 15 of 29	NP_001265045.1
	L1CAM	NM_000425.5		c.1759G>A	p.Gly587Ser	missense	Exon 14 of 28	NP_000416.1
	L1CAM	NM_024003.3		c.1759G>A	p.Gly587Ser	missense	Exon 14 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.1759G>A	p.Gly587Ser	missense	Exon 15 of 29	ENSP00000359077.1
	L1CAM	ENST00000361699.8	TSL:1	c.1759G>A	p.Gly587Ser	missense	Exon 14 of 27	ENSP00000355380.4
	L1CAM	ENST00000361981.7	TSL:1	c.1744G>A	p.Gly582Ser	missense	Exon 13 of 26	ENSP00000354712.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097749 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363163

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40287

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841899

Other (OTH) AF: 0.00 AC: 0 AN: 46091

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 24, 2024

GeneDx

Significance: Uncertain significance

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; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		0.013	Neutral
Varity_R		0.96
gMVP		0.90
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs199888009; hg19: chrX-153133522;