rs80358242
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_015166.4(MLC1):c.176G>A(p.Gly59Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G59G) has been classified as Uncertain significance.
Frequency
Consequence
NM_015166.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLC1 | NM_015166.4 | c.176G>A | p.Gly59Glu | missense_variant, splice_region_variant | 2/12 | ENST00000311597.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLC1 | ENST00000311597.10 | c.176G>A | p.Gly59Glu | missense_variant, splice_region_variant | 2/12 | 1 | NM_015166.4 | P1 | |
MLC1 | ENST00000395876.6 | c.176G>A | p.Gly59Glu | missense_variant, splice_region_variant | 2/12 | 1 | P1 | ||
MLC1 | ENST00000442311.1 | c.176G>A | p.Gly59Glu | missense_variant, splice_region_variant | 2/8 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461604Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727106
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 24, 2023 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 11, 2019 | NM_015166.3(MLC1):c.176G>A(G59E) is classified as likely pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 12189496, 23793458 and 18757878. Classification of NM_015166.3(MLC1):c.176G>A(G59E) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2002 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 14, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2016 | The G59E pathogenic variant in the MLC1 gene has been reported previously in both the homozygous and heterozygous state in individuals with megalencephalic leukoencephalopathy with subcortical cysts (Ben-Zeev et al., 2002). In addition, functional studies of G59E demonstrated reduced expression of the protein at the plasma membrane and reduced protein stability (Duarri et al., 2008). The G59E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G59E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G59E as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 59 of the MLC1 protein (p.Gly59Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with megalencephalic leukoencephalopathy (PMID: 12189496). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4721). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MLC1 function (PMID: 18757878, 23793458). For these reasons, this variant has been classified as Pathogenic. - |
Megalencephalic leukoencephalopathy with subcortical cysts Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2022 | Variant summary: MLC1 c.176G>A (p.Gly59Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249342 control chromosomes. c.176G>A has been reported in the literature to segregate with disease in multiple homozygous individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (Ben-Zeev_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating reduced expression of the protein in the plasma membrane and reduced protein stability (Duarri_2008). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at