ClinVar Genomic variation as it relates to human health
NM_001278116.2(L1CAM):c.719C>T (p.Pro240Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001278116.2(L1CAM):c.719C>T (p.Pro240Leu)
Variation ID: 10001 Accession: VCV000010001.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 153870475 (GRCh38) [ NCBI UCSC ] X: 153135930 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 26, 2017 Apr 15, 2024 Jan 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001278116.2:c.719C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001265045.1:p.Pro240Leu missense NM_000425.5:c.719C>T NP_000416.1:p.Pro240Leu missense NM_001143963.2:c.704C>T NP_001137435.1:p.Pro235Leu missense NM_024003.3:c.719C>T NP_076493.1:p.Pro240Leu missense NC_000023.11:g.153870475G>A NC_000023.10:g.153135930G>A NG_009645.3:g.43749C>T LRG_14t1:c.719C>T LRG_14p1:p.Pro240Leu LRG_14t2:c.719C>T LRG_14p2:p.Pro240Leu P32004:p.Pro240Leu - Protein change
- P240L, P235L
- Other names
- L1CAM, PRO240LEU
- Canonical SPDI
- NC_000023.11:153870474:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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L1CAM | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1227 | 1486 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 24, 2022 | RCV000010684.10 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 27, 2018 | RCV000010683.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2018 | RCV001093004.16 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001257991.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 17, 2023 | RCV003588562.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 27, 2018)
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criteria provided, single submitter
Method: clinical testing
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X-linked hydrocephalus syndrome
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001525999.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 8929944, 16650080]
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Pathogenic
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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X-linked complicated corpus callosum dysgenesis
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557412.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with partial agenesis of corpus callosum (MIM#304100), MASA/CRASH syndrome (MIM#303350) and hydrocephalus due to aqueductal stenosis/with congenital idiopathic intestinal pseudoobstruction/with Hirschsprung disease (MIM#307000). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Both inter and intra-familial variability have been reported (PMID: 7562969, 16650080). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Immunoglobulin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least five unrelated males with a variety of brain abnormalities namely syndromic hydrocephalus (PMID: 8929944), hypoplastic corpus callosum and mild generalized ventriculomegaly (PMID: 16650080) and cerebellar hypoplasia (PMID: 31474318). This variant has been identified and classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 0906 - Segregation evidence for this variant is inconclusive. It has been identified in two brothers with hypoplastic corpus callosum and mild generalized ventriculomegaly (PMID: 16650080). It was also reported to have segregated in 4 affected males across multiple generations in a single family; however, data was not shown (PMID: 8929944). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by quad analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Sep 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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X-linked complicated corpus callosum dysgenesis
Affected status: yes
Allele origin:
maternal
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV003843199.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Method: Exome sequencing
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Pathogenic
(Oct 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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X-linked complicated corpus callosum dysgenesis
Affected status: yes
Allele origin:
maternal
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Eurofins-Biomnis
Accession: SCV003935109.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
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Pathogenic
(Jan 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249773.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Jan 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004298799.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 10001). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data … (more)
ClinVar contains an entry for this variant (Variation ID: 10001). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with clinical features of L1 syndrome (PMID: 8929944, 10797421, 16650080, 31474318). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 240 of the L1CAM protein (p.Pro240Leu). (less)
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Pathogenic
(Feb 18, 2019)
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no assertion criteria provided
Method: research
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Corpus callosum, partial agenesis of, X-linked
Affected status: yes
Allele origin:
germline
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Dobyns Lab, Seattle Children's Research Institute
Accession: SCV000916343.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Number of individuals with the variant: 2
Sex: male
Ethnicity/Population group: Caucasian/Hispanic
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Cerebellar hypoplasia
Affected status: yes
Allele origin:
maternal
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001434804.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
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Pathogenic
(May 01, 2006)
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no assertion criteria provided
Method: literature only
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HYDROCEPHALUS, CONGENITAL, X-LINKED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030909.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In 4 affected males from a family with X-linked hydrocephalus (HYCX; 307000), Gu et al. (1996) identified a 719C-T transition in exon 7 of the … (more)
In 4 affected males from a family with X-linked hydrocephalus (HYCX; 307000), Gu et al. (1996) identified a 719C-T transition in exon 7 of the L1CAM gene, resulting in a pro240-to-leu (P240L) substitution in the third highly conserved Ig-like domain. Three of the older patients had died between 5 and 8 months of age; the proband had adducted thumbs, short stature, severe mental retardation, and spasticity. Basel-Vanagaite et al. (2006) identified the P240L mutation in 2 male sibs with X-linked partial agenesis of the corpus callosum (304100) and mild mental retardation. Neither sib had hydrocephalus, adducted thumbs, or absent speech. The older sib also had Hirschsprung disease and congenital dislocation of the radial heads bilaterally, resulting in limited extension and supination of the elbows. Basel-Vanagaite et al. (2006) emphasized the well-known inter- and intrafamilial phenotypic variability in patients with L1CAM mutations. (less)
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Pathogenic
(May 01, 2006)
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no assertion criteria provided
Method: literature only
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CORPUS CALLOSUM, PARTIAL AGENESIS OF, X-LINKED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030910.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In 4 affected males from a family with X-linked hydrocephalus (HYCX; 307000), Gu et al. (1996) identified a 719C-T transition in exon 7 of the … (more)
In 4 affected males from a family with X-linked hydrocephalus (HYCX; 307000), Gu et al. (1996) identified a 719C-T transition in exon 7 of the L1CAM gene, resulting in a pro240-to-leu (P240L) substitution in the third highly conserved Ig-like domain. Three of the older patients had died between 5 and 8 months of age; the proband had adducted thumbs, short stature, severe mental retardation, and spasticity. Basel-Vanagaite et al. (2006) identified the P240L mutation in 2 male sibs with X-linked partial agenesis of the corpus callosum (304100) and mild mental retardation. Neither sib had hydrocephalus, adducted thumbs, or absent speech. The older sib also had Hirschsprung disease and congenital dislocation of the radial heads bilaterally, resulting in limited extension and supination of the elbows. Basel-Vanagaite et al. (2006) emphasized the well-known inter- and intrafamilial phenotypic variability in patients with L1CAM mutations. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Redefining the Etiologic Landscape of Cerebellar Malformations. | Aldinger KA | American journal of human genetics | 2019 | PMID: 31474318 |
Expanding the phenotypic spectrum of L1CAM-associated disease. | Basel-Vanagaite L | Clinical genetics | 2006 | PMID: 16650080 |
Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease. | Finckh U | American journal of medical genetics | 2000 | PMID: 10797421 |
Five novel mutations in the L1CAM gene in families with X linked hydrocephalus. | Gu SM | Journal of medical genetics | 1996 | PMID: 8929944 |
Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS. | Ruiz JC | Journal of medical genetics | 1995 | PMID: 7562969 |
Text-mined citations for rs137852526 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.