ClinVar Genomic variation as it relates to human health
NM_015166.4(MLC1):c.274C>T (p.Pro92Ser)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015166.4(MLC1):c.274C>T (p.Pro92Ser)
Variation ID: 4719 Accession: VCV000004719.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50080391 (GRCh38) [ NCBI UCSC ] 22: 50518820 (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 2, 2016 Aug 4, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015166.4:c.274C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055981.1:p.Pro92Ser missense NM_001376472.1:c.274C>T NP_001363401.1:p.Pro92Ser missense NM_001376473.1:c.274C>T NP_001363402.1:p.Pro92Ser missense NM_001376474.1:c.274C>T NP_001363403.1:p.Pro92Ser missense NM_001376475.1:c.274C>T NP_001363404.1:p.Pro92Ser missense NM_001376476.1:c.274C>T NP_001363405.1:p.Pro92Ser missense NM_001376477.1:c.274C>T NP_001363406.1:p.Pro92Ser missense NM_001376478.1:c.274C>T NP_001363407.1:p.Pro92Ser missense NM_001376479.1:c.274C>T NP_001363408.1:p.Pro92Ser missense NM_001376480.1:c.184C>T NP_001363409.1:p.Pro62Ser missense NM_001376481.1:c.274C>T NP_001363410.1:p.Pro92Ser missense NM_001376482.1:c.267+2693C>T intron variant NM_001376483.1:c.267+2693C>T intron variant NM_001376484.1:c.37C>T NP_001363413.1:p.Pro13Ser missense NM_139202.3:c.274C>T NP_631941.1:p.Pro92Ser missense NR_164811.1:n.621C>T non-coding transcript variant NR_164812.1:n.405C>T non-coding transcript variant NR_164813.1:n.798C>T non-coding transcript variant NC_000022.11:g.50080391G>A NC_000022.10:g.50518820G>A NG_009162.1:g.10539C>T Q15049:p.Pro92Ser - Protein change
- P92S, P13S, P62S
- Other names
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- Canonical SPDI
- NC_000022.11:50080390:G:A
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00013
Exome Aggregation Consortium (ExAC) 0.00021
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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MLC1 | - | - |
GRCh38 GRCh37 |
664 | 863 |
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
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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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Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000004984.18 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 14, 2024 | RCV001378687.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 24, 2022 | RCV001844006.1 |
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. |
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Likely pathogenic
(Apr 27, 2017)
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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:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000439243.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The MLC1 c.274C>T (p.Pro92Ser) missense variant has been identified in a compound heterozygous state in at least three individuals with megalencephalic leukoencephalopathy, in a heterozygous … (more)
The MLC1 c.274C>T (p.Pro92Ser) missense variant has been identified in a compound heterozygous state in at least three individuals with megalencephalic leukoencephalopathy, in a heterozygous state in two affected individuals in whom a second variant was not identified, and in one affected individual in whom a second variant was found but zygosity was not confirmed (Leegwater et al. 2002; Ben-Zeev et al. 2002; Montagna et al. 2006; Yuzbasioglu et al. 2011). The p.Pro92Ser variant was absent from 240 control alleles and is reported at a frequency of 0.00037 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies using HeLa and COS cells demonstrated reduced surface expression of the p.Pro92Ser-MLC1 protein compared to wild type. The variant protein was confined to late endosomes/lysosomes instead of recycling endosomes (Duarri et al. 2008). Based on the evidence, the p.Pro92Ser variant is classified as likely pathogenic for megalencephalic leukoencephalopathy with subcortical cysts. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(May 02, 2022)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813874.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Jan 14, 2024)
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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: SCV001576310.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 92 of the MLC1 protein (p.Pro92Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 92 of the MLC1 protein (p.Pro92Ser). This variant is present in population databases (rs121908345, gnomAD 0.2%). This missense change has been observed in individuals with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 11935341, 16470554, 21145992). ClinVar contains an entry for this variant (Variation ID: 4719). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLC1 protein function. Experimental studies have shown that this missense change affects MLC1 function (PMID: 18757878, 23793458). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(Mar 19, 2024)
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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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Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV004801424.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
This variant has been identified by standard clinical testing. in trans with MLC1 (NM_015166.4): c.423+1G>T
Number of individuals with the variant: 2
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Likely pathogenic
(Oct 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004153338.8
First in ClinVar: Nov 20, 2023 Last updated: Aug 04, 2024 |
Comment:
MLC1: PM2, PM3, PM5, PP4, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Feb 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Megalencephalic leukoencephalopathy with subcortical cysts
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103896.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: MLC1 c.274C>T (p.Pro92Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: MLC1 c.274C>T (p.Pro92Ser) 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. The variant allele was found at a frequency of 0.00013 in 232710 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLC1 causing Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (0.00013 vs 0.0011), allowing no conclusion about variant significance. c.274C>T has been reported in the literature in multiple individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (example, Leegwater_2002, Ben-Zeev_2002, Montagna_2006). 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 (example Duarri_2008). The most pronounced variant effect results in localization within the lysosomes after internalization from the plasma membrane. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jan 08, 2016)
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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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Counsyl
Accession: SCV000485560.2
First in ClinVar: Oct 02, 2016 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Oct 03, 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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003798989.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
PS3, PM2, PP3
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Pathogenic
(Mar 29, 2024)
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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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Baylor Genetics
Accession: SCV001529596.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024 |
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Pathogenic
(Aug 01, 2002)
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no assertion criteria provided
Method: literature only
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MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025160.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 02, 2016 |
Comment on evidence:
In 3 unrelated families with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), 2 from Croatia and 1 from U.K./Eastern Europe, Leegwater et al. (2002) found … (more)
In 3 unrelated families with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), 2 from Croatia and 1 from U.K./Eastern Europe, Leegwater et al. (2002) found compound heterozygosity for mutations in the MLC1 gene, with 1 of the alleles carrying a pro92-to-ser (P92S) missense mutation. The amino acid change resulted from a C-to-T transition at nucleotide 274. In the U.K./Eastern Europe case, the second mutation was tyr198-to-ter (605908.0008), described by Leegwater et al. (2001). In a family of mixed Jewish ancestry (the father a Libyan Jew and the mother an Ashkenazi Jew) with megalencephalic leukoencephalopathy with subcortical cysts, Ben-Zeev et al. (2002) identified the P92S substitution. The mutation was not found in 140 unaffected Ashkenazi control chromosomes. (less)
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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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Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents. | Capdevila-Nortes X | Human molecular genetics | 2013 | PMID: 23793458 |
GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit. | Jeworutzki E | Neuron | 2012 | PMID: 22405205 |
Novel mutations of the MLC1 gene in Turkish patients. | Yüzbaşioğlu A | European journal of medical genetics | 2011 | PMID: 21145992 |
Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects. | Duarri A | Human molecular genetics | 2008 | PMID: 18757878 |
Vacuolating megalencephalic leukoencephalopathy with subcortical cysts: functional studies of novel variants in MLC1. | Montagna G | Human mutation | 2006 | PMID: 16470554 |
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 rs121908345 ...
HelpRecord last updated Aug 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.