ClinVar Genomic variation as it relates to human health
NM_020533.3(MCOLN1):c.1336G>T (p.Val446Leu)
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(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020533.3(MCOLN1):c.1336G>T (p.Val446Leu)
Variation ID: 208033 Accession: VCV000208033.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 7529689 (GRCh38) [ NCBI UCSC ] 19: 7594575 (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 5, 2015 Jan 25, 2025 Mar 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020533.3:c.1336G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065394.1:p.Val446Leu missense NC_000019.10:g.7529689G>T NC_000019.9:g.7594575G>T NG_013374.1:g.538G>T NG_015806.1:g.12080G>T Q9GZU1:p.Val446Leu - Protein change
- V446L
- Other names
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- Canonical SPDI
- NC_000019.10:7529688:G: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.
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Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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MCOLN1 | - | - |
GRCh38 GRCh37 |
850 | 889 |
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
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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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Conflicting classifications of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 25, 2024 | RCV000194491.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 4, 2020 | RCV001266563.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2024 | RCV005025309.1 |
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
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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
(Feb 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444739.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The alteration results in an amino acid change:_x000D_ _x000D_ The c.1336G>T (p.V446L) alteration is located in coding exon 11 of the MCOLN1 gene. This alteration … (more)
The alteration results in an amino acid change:_x000D_ _x000D_ The c.1336G>T (p.V446L) alteration is located in coding exon 11 of the MCOLN1 gene. This alteration results from a G to T substitution at nucleotide position 1336, causing the valine (V) at amino acid position 446 to be replaced by a leucine (L). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.1336G>T alteration was observed in 0.0016% (4/251458) of total alleles studied, with a frequency of 0.012% (4/34592) in the Latino subpopulation. The amino acid change has been observed in affected individuals: _x000D_ _x000D_ This alteration has been observed homozygous in a patient with a severe presentation of mucolipidosis IV (Sun, 2000; Wakabayashi, 2011; Yamaguchi, 2019). Functional analysis reveals there may be a damaging effect of the amino acid alteration: _x000D_ _x000D_ Several studies have demonstrated using functional data that the p.V446L alteration can interfere with correct subcellular localization (Dong, 2008; Chen, 2014; Pryor, 2006). Other studies suggest the alteration impairs channel function (Dong, 2008), but this was not consistently observed (Raychowdhury, 2004). Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Likely pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mucolipidosis type IV
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338200.6
First in ClinVar: Jun 18, 2020 Last updated: Jun 29, 2024 |
Comment:
Variant summary: MCOLN1 c.1336G>T (p.Val446Leu) results in a conservative amino acid change located in the polycystin cation channel, PKD1/PKD2 domain (IPR013122) of the encoded protein … (more)
Variant summary: MCOLN1 c.1336G>T (p.Val446Leu) results in a conservative amino acid change located in the polycystin cation channel, PKD1/PKD2 domain (IPR013122) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251458 control chromosomes (gnomAD). c.1336G>T has been reported in the literature in at least one homozygous individual from a consanguineous family affected with Mucolipidosis Type 4 (Sun_2000). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in resistance to the inhibition of ion channel activity at low pH (Roychowdhury_2004), significantly reduced co-localization to lysosomes (Chen_2014), and impaired cationic iron permeability resulting in <10% of normal activity (Dong_2008). The following publications have been ascertained in the context of this evaluation (PMID: 11030752, 18794901, 14749347, 25119295). ClinVar contains an entry for this variant (Variation ID: 208033). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mucolipidosis type IV
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003443094.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 208033). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
ClinVar contains an entry for this variant (Variation ID: 208033). 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 MCOLN1 protein function. Experimental studies have shown that this missense change affects MCOLN1 function (PMID: 14749347, 18794901, 25119295, 27670435). 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. This missense change has been observed in individual(s) with mucolipidosis type IV (PMID: 11030752). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 446 of the MCOLN1 protein (p.Val446Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). (less)
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Likely pathogenic
(Mar 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mucolipidosis type IV
Lisch epithelial corneal dystrophy
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Fulgent Genetics, Fulgent Genetics
Accession: SCV005648827.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
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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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Novel compound heterozygous MCOLN1 mutations identified in a Japanese girl with severe developmental delay and thin corpus callosum. | Yamaguchi N | Brain & development | 2020 | PMID: 31899079 |
BK channel agonist represents a potential therapeutic approach for lysosomal storage diseases. | Zhong XZ | Scientific reports | 2016 | PMID: 27670435 |
A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV. | Chen CC | Nature communications | 2014 | PMID: 25119295 |
Mucolipidosis type IV: an update. | Wakabayashi K | Molecular genetics and metabolism | 2011 | PMID: 21763169 |
The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. | Dong XP | Nature | 2008 | PMID: 18794901 |
Isolated ocular disease is associated with decreased mucolipin-1 channel conductance. | Goldin E | Investigative ophthalmology & visual science | 2008 | PMID: 18326692 |
Mucolipin-1 is a lysosomal membrane protein required for intracellular lactosylceramide traffic. | Pryor PR | Traffic (Copenhagen, Denmark) | 2006 | PMID: 16978393 |
Overexpression of wild-type and mutant mucolipin proteins in mammalian cells: effects on the late endocytic compartment organization. | Manzoni M | FEBS letters | 2004 | PMID: 15178326 |
Molecular pathophysiology of mucolipidosis type IV: pH dysregulation of the mucolipin-1 cation channel. | Raychowdhury MK | Human molecular genetics | 2004 | PMID: 14749347 |
Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. | Sun M | Human molecular genetics | 2000 | PMID: 11030752 |
Text-mined citations for rs754097561 ...
HelpRecord last updated Feb 01, 2025
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.