ClinVar Genomic variation as it relates to human health
NM_015166.4(MLC1):c.240G>A (p.Met80Ile)
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.
Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015166.4(MLC1):c.240G>A (p.Met80Ile)
Variation ID: 68790 Accession: VCV000068790.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50083111 (GRCh38) [ NCBI UCSC ] 22: 50521540 (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 Oct 31, 2013 Sep 3, 2023 Jul 4, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015166.4:c.240G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055981.1:p.Met80Ile missense NM_001376472.1:c.240G>A NP_001363401.1:p.Met80Ile missense NM_001376473.1:c.240G>A NP_001363402.1:p.Met80Ile missense NM_001376474.1:c.240G>A NP_001363403.1:p.Met80Ile missense NM_001376475.1:c.240G>A NP_001363404.1:p.Met80Ile missense NM_001376476.1:c.240G>A NP_001363405.1:p.Met80Ile missense NM_001376477.1:c.240G>A NP_001363406.1:p.Met80Ile missense NM_001376478.1:c.240G>A NP_001363407.1:p.Met80Ile missense NM_001376479.1:c.240G>A NP_001363408.1:p.Met80Ile missense NM_001376480.1:c.177+1615G>A intron variant NM_001376481.1:c.240G>A NP_001363410.1:p.Met80Ile missense NM_001376482.1:c.240G>A NP_001363411.1:p.Met80Ile missense NM_001376483.1:c.240G>A NP_001363412.1:p.Met80Ile missense NM_001376484.1:c.3G>A NP_001363413.1:p.Met1Ile missense initiator codon variant NM_139202.3:c.240G>A NP_631941.1:p.Met80Ile missense NR_164811.1:n.587G>A non-coding transcript variant NR_164812.1:n.371G>A non-coding transcript variant NR_164813.1:n.764G>A non-coding transcript variant NC_000022.11:g.50083111C>T NC_000022.10:g.50521540C>T NG_009162.1:g.7819G>A Q15049:p.Met80Ile - Protein change
- M80I, M1I
- Other names
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- Canonical SPDI
- NC_000022.11:50083110:C:T
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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LOC125446261 | - | - | - | GRCh38 | - | 119 |
MLC1 | - | - |
GRCh38 GRCh37 |
646 | 844 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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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Uncertain significance (2) |
criteria provided, single submitter
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Jun 25, 2022 | RCV000059742.2 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 4, 2022 | RCV001810419.5 |
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
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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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Likely pathogenic
(May 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Megalencephalic leukoencephalopathy with subcortical cysts 1
(Autosomal 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: SCV002768619.2
First in ClinVar: Dec 24, 2022 Last updated: Sep 03, 2023 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Jun 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003444349.2
First in ClinVar: Feb 07, 2023 Last updated: Sep 03, 2023 |
Comment:
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). … (more)
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. (less)
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Likely pathogenic
(Jul 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Megalencephalic leukoencephalopathy with subcortical cysts 1
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807737.2
First in ClinVar: Mar 04, 2023 Last updated: Sep 03, 2023 |
Comment:
ACMG classification criteria: PS4 supporting, PM2 moderated, PM3 strong, PP3 supporting
Number of individuals with the variant: 1
Clinical Features:
Lower limb muscle weakness (present) , Dysmetria (present) , Gait ataxia (present) , Obesity (present) , Impaired tandem gait (present) , Macrocephaly (present) , Neonatal … (more)
Lower limb muscle weakness (present) , Dysmetria (present) , Gait ataxia (present) , Obesity (present) , Impaired tandem gait (present) , Macrocephaly (present) , Neonatal hypotonia (present) , Premature birth (present) , Global developmental delay (present) , Dysdiadochokinesis (present) , Seizure (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Uncertain significance
(Nov 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Megalencephalic leukoencephalopathy with subcortical cysts 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV002060154.3
First in ClinVar: Jan 15, 2022 Last updated: Sep 03, 2023 |
Comment:
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 … (more)
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. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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UniProtKB/Swiss-Prot
Accession: SCV000091312.2
First in ClinVar: Oct 31, 2013 Last updated: Sep 03, 2023 |
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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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Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1. | Ilja Boor PK | Human mutation | 2006 | PMID: 16652334 |
Vacuolating megalencephalic leukoencephalopathy with subcortical cysts: functional studies of novel variants in MLC1. | Montagna G | Human mutation | 2006 | PMID: 16470554 |
Text-mined citations for rs281875310 ...
HelpRecord last updated Feb 04, 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.