This missense change has been observed in individual(s) with MLC1-related conditions (PMID: 21555057, 31069529, 32209057). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 320 of the MLC1 protein (p.Thr320Lys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 68797). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MLC1 protein function. 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.
ClinVar Genomic variation as it relates to human health
NM_015166.4(MLC1):c.959C>A (p.Thr320Lys)
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.
(6)
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/Likely pathogenic
6
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.959C>A (p.Thr320Lys)
Variation ID: 68797 Accession: VCV000068797.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q13.33 22: 50064134 (GRCh38) [ NCBI UCSC ] 22: 50502563 (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 Oct 31, 2013 Aug 11, 2024 May 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_015166.4:c.959C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055981.1:p.Thr320Lys missense NM_001376472.1:c.959C>A NP_001363401.1:p.Thr320Lys missense NM_001376473.1:c.959C>A NP_001363402.1:p.Thr320Lys missense NM_001376474.1:c.959C>A NP_001363403.1:p.Thr320Lys missense NM_001376475.1:c.959C>A NP_001363404.1:p.Thr320Lys missense NM_001376476.1:c.959C>A NP_001363405.1:p.Thr320Lys missense NM_001376477.1:c.959C>A NP_001363406.1:p.Thr320Lys missense NM_001376478.1:c.959C>A NP_001363407.1:p.Thr320Lys missense NM_001376479.1:c.902C>A NP_001363408.1:p.Thr301Lys missense NM_001376480.1:c.869C>A NP_001363409.1:p.Thr290Lys missense NM_001376481.1:c.857C>A NP_001363410.1:p.Thr286Lys missense NM_001376482.1:c.803C>A NP_001363411.1:p.Thr268Lys missense NM_001376483.1:c.803C>A NP_001363412.1:p.Thr268Lys missense NM_001376484.1:c.722C>A NP_001363413.1:p.Thr241Lys missense NM_139202.3:c.959C>A NP_631941.1:p.Thr320Lys missense NR_164811.1:n.1306C>A non-coding transcript variant NR_164812.1:n.1090C>A non-coding transcript variant NR_164813.1:n.1483C>A non-coding transcript variant NC_000022.11:g.50064134G>T NC_000022.10:g.50502563G>T NG_009162.1:g.26796C>A Q15049:p.Thr320Lys - Protein change
- T320K, T241K, T268K, T286K, T290K, T301K
- Other names
- -
- Canonical SPDI
- NC_000022.11:50064133:G:T
-
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
|
Aug 18, 2023 | RCV000059749.3 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 3, 2022 | RCV000411937.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 22, 2024 | RCV004689442.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Sep 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Megalencephalic leukoencephalopathy with subcortical cysts 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004195011.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Likely pathogenic
(Aug 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004300041.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with MLC1-related conditions (PMID: 21555057, 31069529, 32209057). This sequence change replaces threonine, which is neutral and polar, … (more)
This missense change has been observed in individual(s) with MLC1-related conditions (PMID: 21555057, 31069529, 32209057). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 320 of the MLC1 protein (p.Thr320Lys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 68797). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MLC1 protein function. 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)
|
|
|
Pathogenic
(May 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Megalencephalic leukoencephalopathy with subcortical cysts
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005185082.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
Variant summary: MLC1 c.959C>A (p.Thr320Lys) 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.959C>A (p.Thr320Lys) 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 was absent in 245644 control chromosomes (gnomAD). c.959C>A has been reported in the literature in multiple homozygous individuals affected with megalencephalic leukoencephalopathy with subcortical cysts 1 and in several families, the variant segregated with the disease (examples: Boor_2006, Ilyas_2020, Shukla_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16652334, 32209057, 21555057). ClinVar contains an entry for this variant (Variation ID: 68797). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Aug 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Megalencephalic leukoencephalopathy with subcortical cysts 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000486784.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Likely pathogenic
(Oct 08, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Megalencephalic leukoencephalopathy with subcortical cysts 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Biological Sciences, International Islamic University, Islamabad
Accession: SCV001167373.2
First in ClinVar: Mar 16, 2020 Last updated: Mar 11, 2023 |
Comment:
The mutation was identified after the exome Sequencing of the patient collected from Pakistan. Rare variants are filtered out with an allelic frequency of less … (more)
The mutation was identified after the exome Sequencing of the patient collected from Pakistan. Rare variants are filtered out with an allelic frequency of less than 1%. Only MLC1 gene mutation showing co-segregation with family. (less)
Age: 0-9 years
Ethnicity/Population group: South Asian
Geographic origin: Pakistan
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
UniProtKB/Swiss-Prot
Accession: SCV000091319.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
|
Comment:
Comment:
Variant summary: MLC1 c.959C>A (p.Thr320Lys) 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 was absent in 245644 control chromosomes (gnomAD). c.959C>A has been reported in the literature in multiple homozygous individuals affected with megalencephalic leukoencephalopathy with subcortical cysts 1 and in several families, the variant segregated with the disease (examples: Boor_2006, Ilyas_2020, Shukla_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16652334, 32209057, 21555057). ClinVar contains an entry for this variant (Variation ID: 68797). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The mutation was identified after the exome Sequencing of the patient collected from Pakistan. Rare variants are filtered out with an allelic frequency of less than 1%. Only MLC1 gene mutation showing co-segregation with family.
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:
This missense change has been observed in individual(s) with MLC1-related conditions (PMID: 21555057, 31069529, 32209057). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 320 of the MLC1 protein (p.Thr320Lys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 68797). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MLC1 protein function. 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.
Comment:
Variant summary: MLC1 c.959C>A (p.Thr320Lys) 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 was absent in 245644 control chromosomes (gnomAD). c.959C>A has been reported in the literature in multiple homozygous individuals affected with megalencephalic leukoencephalopathy with subcortical cysts 1 and in several families, the variant segregated with the disease (examples: Boor_2006, Ilyas_2020, Shukla_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16652334, 32209057, 21555057). ClinVar contains an entry for this variant (Variation ID: 68797). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The mutation was identified after the exome Sequencing of the patient collected from Pakistan. Rare variants are filtered out with an allelic frequency of less than 1%. Only MLC1 gene mutation showing co-segregation with family.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Novel variants underlying autosomal recessive intellectual disability in Pakistani consanguineous families. | Ilyas M | BMC medical genetics | 2020 | PMID: 32209057 |
| Multi-gene testing in neurological disorders showed an improved diagnostic yield: data from over 1000 Indian patients. | Ganapathy A | Journal of neurology | 2019 | PMID: 31069529 |
| Molecular genetic studies in Indian patients with megalencephalic leukoencephalopathy. | Shukla P | Pediatric neurology | 2011 | PMID: 21555057 |
| Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1. | Ilja Boor PK | Human mutation | 2006 | PMID: 16652334 |
Text-mined citations for rs281875313 ...
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.