The c.135dupC variant in the MLC1 gene has been reported in the homozygous state in several unrelated patients with MLC (Leegwater et al., 2002; Ben-Zeev et al., 2002; Ridder et al., 2011; Saini et al., 2015). The c.135dupC variant causes a frameshift starting with codon Cysteine 46, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 34 of the new reading frame, denoted p.Cys46LeufsX34. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.135dupC variant is observed in 7/245210 (0.003%) alleles in large population cohorts We interpret c.135dupC as a pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_015166.4(MLC1):c.135dup (p.Cys46fs)
Germline
Classification
Help
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.
(10)
Help
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.
Pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_015166.4(MLC1):c.135dup (p.Cys46fs)
Variation ID: 4722 Accession: VCV000004722.22
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 22q13.33 22: 50084767-50084768 (GRCh38) [ NCBI UCSC ] 22: 50523196-50523197 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 3, 2013 Jun 17, 2024 Feb 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_015166.4:c.135dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055981.1:p.Cys46fs frameshift NM_015166.4:c.135dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001376472.1:c.135dup NP_001363401.1:p.Cys46fs frameshift NM_001376473.1:c.135dup NP_001363402.1:p.Cys46fs frameshift NM_001376474.1:c.135dup NP_001363403.1:p.Cys46fs frameshift NM_001376475.1:c.135dup NP_001363404.1:p.Cys46fs frameshift NM_001376476.1:c.135dup NP_001363405.1:p.Cys46fs frameshift NM_001376477.1:c.135dup NP_001363406.1:p.Cys46fs frameshift NM_001376478.1:c.135dup NP_001363407.1:p.Cys46fs frameshift NM_001376479.1:c.135dup NP_001363408.1:p.Cys46fs frameshift NM_001376480.1:c.135dup NP_001363409.1:p.Cys46fs frameshift NM_001376481.1:c.135dup NP_001363410.1:p.Cys46fs frameshift NM_001376482.1:c.135dup NP_001363411.1:p.Cys46fs frameshift NM_001376483.1:c.135dup NP_001363412.1:p.Cys46fs frameshift NM_001376484.1:c.-59+587dup intron variant NM_015166.3:c.135dupC NM_139202.3:c.135dup NP_631941.1:p.Cys46fs frameshift NM_139202.3:c.135dupC NR_164811.1:n.482dup non-coding transcript variant NR_164812.1:n.266dup non-coding transcript variant NR_164813.1:n.659dup non-coding transcript variant NC_000022.11:g.50084773dup NC_000022.10:g.50523202dup NG_009162.1:g.6162dup - Protein change
- C46fs
- Other names
- -
- Canonical SPDI
- NC_000022.11:50084767:GGGGGG:GGGGGGG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| MLC1 | - | - |
GRCh38 GRCh37 |
665 | 864 | |
Conditions - Germline
| Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Feb 17, 2024 | RCV000004987.19 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 11, 2023 | RCV000599600.7 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2020 | RCV001274276.1 |
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
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000710387.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Comment:
The c.135dupC variant in the MLC1 gene has been reported in the homozygous state in several unrelated patients with MLC (Leegwater et al., 2002; Ben-Zeev … (more)
The c.135dupC variant in the MLC1 gene has been reported in the homozygous state in several unrelated patients with MLC (Leegwater et al., 2002; Ben-Zeev et al., 2002; Ridder et al., 2011; Saini et al., 2015). The c.135dupC variant causes a frameshift starting with codon Cysteine 46, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 34 of the new reading frame, denoted p.Cys46LeufsX34. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.135dupC variant is observed in 7/245210 (0.003%) alleles in large population cohorts We interpret c.135dupC as a pathogenic variant. (less)
|
|
|
Pathogenic
(Dec 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Megalencephalic leukoencephalopathy with subcortical cysts 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194053.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is classified as pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 15037685, 14572144, … (more)
NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is classified as pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 15037685, 14572144, 22006981, 12189496 and 11935341. Classification of NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Megalencephalic leukoencephalopathy with subcortical cysts 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001573208.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Sex: male
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Megalencephalic leukoencephalopathy with subcortical cysts 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003925691.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Comment:
A Homozygote Frameshift variant c.135dupC in Exon 2 of the MLC1 gene that results in the amino acid substitution p.Cys46fs*34 was identified. The observed variant … (more)
A Homozygote Frameshift variant c.135dupC in Exon 2 of the MLC1 gene that results in the amino acid substitution p.Cys46fs*34 was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and and novel in 1KG, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease- causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 4722]. The observed variation has been previously reported in individuals with megalencephalic leukoencephalopathy (Shukla P, et.al., 2011). For these reasons, this variant has been classified as Pathogenic. (less)
Ethnicity/Population group: Asian
Geographic origin: India
|
|
|
Pathogenic
(Feb 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Megalencephalic leukoencephalopathy with subcortical cysts 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003821540.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Oct 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000963504.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys46Leufs*34) in the MLC1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Cys46Leufs*34) in the MLC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLC1 are known to be pathogenic (PMID: 11254442, 16470554, 24824219). This variant is present in population databases (rs80358241, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with megalencephalic leukoencephalopathy (PMID: 11935341, 12189496, 21555057). ClinVar contains an entry for this variant (Variation ID: 4722). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Megalencephalic leukoencephalopathy with subcortical cysts 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194971.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Aug 01, 2002)
|
no assertion criteria provided
Method: literature only
|
MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025163.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 02, 2016 |
Comment on evidence:
In a patient of Indian Agrawali ancestry with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), Ben-Zeev et al. (2002) identified a homozygous insertion of a … (more)
In a patient of Indian Agrawali ancestry with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), Ben-Zeev et al. (2002) identified a homozygous insertion of a cytosine at nucleotide 135 at exon 2 of the MLC1 gene. This resulted in a frameshift and the creation of a stop codon 104 bp downstream. Leegwater et al. (2002) described this mutation in 3 Agrawali patients. They stated that the disease was probably introduced into the tribe by a single founder, and the mutation is probably shared by all MLC patients of this community. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Megalencephalic leukoencephalopathy with subcortical cysts
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001458247.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Megalencephalic leukoencephalopathy with subcortical cysts 1
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000041274.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is classified as pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 15037685, 14572144, 22006981, 12189496 and 11935341. Classification of NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Comment:
A Homozygote Frameshift variant c.135dupC in Exon 2 of the MLC1 gene that results in the amino acid substitution p.Cys46fs*34 was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and and novel in 1KG, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease- causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 4722]. The observed variation has been previously reported in individuals with megalencephalic leukoencephalopathy (Shukla P, et.al., 2011). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Cys46Leufs*34) in the MLC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLC1 are known to be pathogenic (PMID: 11254442, 16470554, 24824219). This variant is present in population databases (rs80358241, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with megalencephalic leukoencephalopathy (PMID: 11935341, 12189496, 21555057). ClinVar contains an entry for this variant (Variation ID: 4722). For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
The c.135dupC variant in the MLC1 gene has been reported in the homozygous state in several unrelated patients with MLC (Leegwater et al., 2002; Ben-Zeev et al., 2002; Ridder et al., 2011; Saini et al., 2015). The c.135dupC variant causes a frameshift starting with codon Cysteine 46, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 34 of the new reading frame, denoted p.Cys46LeufsX34. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.135dupC variant is observed in 7/245210 (0.003%) alleles in large population cohorts We interpret c.135dupC as a pathogenic variant.
Comment:
NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is classified as pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 15037685, 14572144, 22006981, 12189496 and 11935341. Classification of NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Comment:
A Homozygote Frameshift variant c.135dupC in Exon 2 of the MLC1 gene that results in the amino acid substitution p.Cys46fs*34 was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and and novel in 1KG, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease- causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 4722]. The observed variation has been previously reported in individuals with megalencephalic leukoencephalopathy (Shukla P, et.al., 2011). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Cys46Leufs*34) in the MLC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLC1 are known to be pathogenic (PMID: 11254442, 16470554, 24824219). This variant is present in population databases (rs80358241, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with megalencephalic leukoencephalopathy (PMID: 11935341, 12189496, 21555057). ClinVar contains an entry for this variant (Variation ID: 4722). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Megalencephalic Leukoencephalopathy with Subcortical Cysts. | Adam MP | - | 2023 | PMID: 20301707 |
| Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans. | Sirisi S | Human molecular genetics | 2014 | PMID: 24824219 |
| Megalencephalic leucoencephalopathy with cysts: defect in chloride currents and cell volume regulation. | Ridder MC | Brain : a journal of neurology | 2011 | PMID: 22006981 |
| Molecular genetic studies in Indian patients with megalencephalic leukoencephalopathy. | Shukla P | Pediatric neurology | 2011 | PMID: 21555057 |
| Vacuolating megalencephalic leukoencephalopathy with subcortical cysts: functional studies of novel variants in MLC1. | Montagna G | Human mutation | 2006 | PMID: 16470554 |
| Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation. | Gorospe JR | Neurology | 2004 | PMID: 15037685 |
| Megalencephalic leukoencephalopathy with subcortical cysts. | Singhal BS | Journal of child neurology | 2003 | PMID: 14572144 |
| Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews. | Ben-Zeev B | Human genetics | 2002 | PMID: 12189496 |
| Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts. | Leegwater PA | Human genetics | 2002 | PMID: 11935341 |
| Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. | Leegwater PA | American journal of human genetics | 2001 | PMID: 11254442 |
Text-mined citations for rs80358241 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.