chrX-153862856-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_001278116.2(L1CAM):c.3581C>T(p.Ser1194Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,854 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S1194S) has been classified as Likely benign.
Frequency
Consequence
NM_001278116.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
L1CAM | NM_001278116.2 | c.3581C>T | p.Ser1194Leu | missense_variant | 29/29 | ENST00000370060.7 | |
L1CAM | NM_000425.5 | c.3581C>T | p.Ser1194Leu | missense_variant | 28/28 | ||
L1CAM | NM_024003.3 | c.3569C>T | p.Ser1190Leu | missense_variant | 27/27 | ||
L1CAM | NM_001143963.2 | c.3554C>T | p.Ser1185Leu | missense_variant | 26/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
L1CAM | ENST00000370060.7 | c.3581C>T | p.Ser1194Leu | missense_variant | 29/29 | 5 | NM_001278116.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1097854Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 363230
GnomAD4 genome Cov.: 24
ClinVar
Submissions by phenotype
X-linked hydrocephalus syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1994 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics Institute, Tel Aviv Sourasky Medical Center | May 12, 2021 | - - |
MASA syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1994 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 07, 2015 | The p.S1194L variant (also known as c.3581C>T) is located in exon 28 of the L1CAM gene. This alteration results from a C to T substitution at nucleotide position 3581. The serine at codon 1194 is replaced by leucine, an amino acid with dissimilar properties. In one published study, this variant was observed to segregate with disease in two maternally related male probands diagnosed with MASA syndrome and two obligate carrier females and was absent in two unaffected maternally related males. An additional affected male in this family was diagnosed with congenital hydrocephalus, extreme macrocephaly, severe spasticity, and MR (HSAS) but died at age 15 years and was untested in this family study (Fransen, E et al. Hum Mol Genet 1994;3:2255-2256). This variant has been observed in a male proband tested by our laboratory diagnosed with macrocephaly, agenesis of the corpus collosum, and periventricular volume loss on MRI and whose family history consististed of two maternally related males in separate generations diagnosed with hydrocephalus and mental retardation respectively. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, its clinical significance remains unclear. - |
Hydrops fetalis;C3278123:Severe hydrocephalus Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Reproductive Medicine, Peking University Third Hospital | Oct 16, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 31, 2022 | Published functional studies demonstrate a damaging effect due to reduction of neuronal migration and MAP kinase activation (Thelen et al., 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11438988, 10908608, 11222639, 28152038, 7881431, 30197081, 31680349, 12077189) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at