NM_001278116.2:c.1219C>T

Variant names:

• chrX-153869568-G-A
• rs782756293
• NM_001278116.2:c.1219C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_001278116.2(L1CAM):​c.1219C>T​(p.Arg407Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,096,695 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R407H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.506
• 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001278116.2
• BP6: Variant X-153869568-G-A is Benign according to our data. Variant chrX-153869568-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568459.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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.1219C>T	p.Arg407Cys	missense	Exon 11 of 29	NP_001265045.1
	L1CAM	NM_000425.5		c.1219C>T	p.Arg407Cys	missense	Exon 10 of 28	NP_000416.1
	L1CAM	NM_024003.3		c.1219C>T	p.Arg407Cys	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.1219C>T	p.Arg407Cys	missense	Exon 11 of 29	ENSP00000359077.1
	L1CAM	ENST00000361699.8	TSL:1	c.1219C>T	p.Arg407Cys	missense	Exon 10 of 27	ENSP00000355380.4
	L1CAM	ENST00000361981.7	TSL:1	c.1204C>T	p.Arg402Cys	missense	Exon 9 of 26	ENSP00000354712.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.0000224 AC: 4 AN: 178588 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1096695 Hom.: 0 Cov.: 33 AF XY: 0.00000552 AC XY: 2 AN XY: 362357

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.0000285 AC: 1 AN: 35106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19213

East Asian (EAS) AF: 0.0000663 AC: 2 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 53697

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841618

Other (OTH) AF: 0.00 AC: 0 AN: 46027

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Nov 30, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25641508)

Spastic paraplegia Benign:1

Aug 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

L1CAM-related disorder Benign:1

Aug 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.51
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.64		Loss of disorder (P = 0.0986)
MVP		0.76
MPC		1.7
ClinPred		0.48	T
GERP RS		4.5
Varity_R		0.48
gMVP		0.94
Mutation Taster		=77/23	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: rs782756293; hg19: chrX-153135023; COSMIC: COSV62830614; COSMIC: COSV62830614;