rs281875310
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_015166.4(MLC1):c.240G>A(p.Met80Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,006 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MLC1
NM_015166.4 missense
NM_015166.4 missense
Scores
10
7
1
Clinical Significance
Conservation
PhyloP100: 7.21
Genes affected
MLC1 (HGNC:17082): (modulator of VRAC current 1) The function of this gene product is unknown; however, homology to other proteins suggests that it may be an integral membrane transporter. Mutations in this gene have been associated with megalencephalic leukoencephalopathy with subcortical cysts, an autosomal recessive neurological disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_015166.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
?
Variant 22-50083111-C-T is Pathogenic according to our data. Variant chr22-50083111-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68790.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2, not_provided=1}. Variant chr22-50083111-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLC1 | NM_015166.4 | c.240G>A | p.Met80Ile | missense_variant | 3/12 | ENST00000311597.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLC1 | ENST00000311597.10 | c.240G>A | p.Met80Ile | missense_variant | 3/12 | 1 | NM_015166.4 | P1 | |
MLC1 | ENST00000395876.6 | c.240G>A | p.Met80Ile | missense_variant | 3/12 | 1 | P1 | ||
MLC1 | ENST00000442311.1 | c.177+1615G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251256Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135840
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461848Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727218
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | A homozygous missense variant was identified, NM_015166.3(MLC1):c.240G>A in exon 3 of 12 of the MLC1 gene. This substitution is predicted to create a minor amino acid change from a methionine to an isoleucine at position 80 of the protein, NP_055981.1(MLC1):p.(Met80Ile). The methionine at this position has very high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). The variant has previously been reported in two patients with megalencephalic leukoencephalopathy with subcortical cysts (ClinVar, Ilja Boor, P., et al. (2006)). A different variant in the same codon resulting in a change to a valine, p.(Met80Val), has also been reported in a patient with the same condition (Montagna, G. et al. (2006). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jul 04, 2022 | ACMG classification criteria: PS4 supporting, PM2 moderated, PM3 strong, PP3 supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 08, 2021 | NM_015166.3(MLC1):c.240G>A(M80I) is a missense variant classified as a variant of uncertain significance in the context of megalencephalic leukoencephalopathy with subcortical cysts. M80I has been observed in cases with relevant disease (PMID: 16652334). Functional assessments of this variant are not available in the literature. M80I has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, there is insufficient evidence to classify NM_015166.3(MLC1):c.240G>A(M80I) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 25, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 80 of the MLC1 protein (p.Met80Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of megalencephalic leukoencephalopathy with subcortical cysts (PMID: 16652334; Invitae). ClinVar contains an entry for this variant (Variation ID: 68790). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Met80 amino acid residue in MLC1. Other variant(s) that disrupt this residue have been observed in individuals with MLC1-related conditions (PMID: 16470554), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 02, 2024 | Variant summary: MLC1 c.240G>A (p.Met80Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251256 control chromosomes. c.240G>A has been reported in the literature as a homozygous genotype in at-least one individual affected with features of Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (example, Boor_2006 cited in Batool_2022). The same study also reports a non-informative heterozygous genotype in at-least one unrelated affected individual. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34918859, 16652334, 23079554). ClinVar contains an entry for this variant (Variation ID: 68790). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
P;P
Vest4
MutPred
Loss of catalytic residue at V75 (P = 0.4162);Loss of catalytic residue at V75 (P = 0.4162);
MVP
MPC
0.90
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at