Variant summary: MCOLN1 c.920delT (p.Leu307ProfsX65) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251390 control chromosomes (gnomAD). c.920delT has been reported in the literature in one individual affected with Mucolipidosis Type 4 (Goldin_2008). These data indicate that the variant may be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_020533.3(MCOLN1):c.920del (p.Leu307fs)
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_020533.3(MCOLN1):c.920del (p.Leu307fs)
Variation ID: 208039 Accession: VCV000208039.16
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 7528639 (GRCh38) [ NCBI UCSC ] 19: 7593525 (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 May 1, 2024 Dec 12, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020533.3:c.920del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065394.1:p.Leu307fs frameshift NM_020533.2:c.920del NC_000019.10:g.7528639del NC_000019.9:g.7593525del NG_015806.1:g.11030del - Protein change
- L307fs
- Other names
- -
- Canonical SPDI
- NC_000019.10:7528638: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- 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. |
|||
| MCOLN1 | - | - |
GRCh38 GRCh37 |
839 | 877 | |
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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 12, 2023 | RCV000194725.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 4, 2023 | RCV004020300.1 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Jan 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type IV
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000485607.2
First in ClinVar: Oct 05, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jul 30, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type IV
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001427011.1
First in ClinVar: Aug 10, 2020 Last updated: Aug 10, 2020 |
Comment:
Variant summary: MCOLN1 c.920delT (p.Leu307ProfsX65) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MCOLN1 c.920delT (p.Leu307ProfsX65) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251390 control chromosomes (gnomAD). c.920delT has been reported in the literature in one individual affected with Mucolipidosis Type 4 (Goldin_2008). These data indicate that the variant may be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Feb 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type IV
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002812699.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type IV
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000938348.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu307Profs*65) in the MCOLN1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Leu307Profs*65) in the MCOLN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MCOLN1 are known to be pathogenic (PMID: 11030752, 11317355, 37972748). This variant is present in population databases (rs755042147, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with mucolipidosis type IV (PMID: 18326692). ClinVar contains an entry for this variant (Variation ID: 208039). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Dec 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004904790.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.920delT (p.L307Pfs*65) alteration, located in exon 8 (coding exon 8) of the MCOLN1 gene, consists of a deletion of one nucleotide at position 920, … (more)
The c.920delT (p.L307Pfs*65) alteration, located in exon 8 (coding exon 8) of the MCOLN1 gene, consists of a deletion of one nucleotide at position 920, causing a translational frameshift with a predicted alternate stop codon after 65 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.920delT allele has an overall frequency of 0.001% (4/282790) total alleles studied. The highest observed frequency was 0.003% (4/129108) of European (non-Finnish) alleles. This variant has been reported compound heterozygous in one individual with features consistent with Mucolipidosis IV (Goldin, 2008). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
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Pathogenic
(Nov 29, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Mucolipidosis type IV
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002091385.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Leu307Profs*65) in the MCOLN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MCOLN1 are known to be pathogenic (PMID: 11030752, 11317355, 37972748). This variant is present in population databases (rs755042147, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with mucolipidosis type IV (PMID: 18326692). ClinVar contains an entry for this variant (Variation ID: 208039). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.920delT (p.L307Pfs*65) alteration, located in exon 8 (coding exon 8) of the MCOLN1 gene, consists of a deletion of one nucleotide at position 920, causing a translational frameshift with a predicted alternate stop codon after 65 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.920delT allele has an overall frequency of 0.001% (4/282790) total alleles studied. The highest observed frequency was 0.003% (4/129108) of European (non-Finnish) alleles. This variant has been reported compound heterozygous in one individual with features consistent with Mucolipidosis IV (Goldin, 2008). Based on the available evidence, this alteration is 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:
Variant summary: MCOLN1 c.920delT (p.Leu307ProfsX65) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251390 control chromosomes (gnomAD). c.920delT has been reported in the literature in one individual affected with Mucolipidosis Type 4 (Goldin_2008). These data indicate that the variant may be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Leu307Profs*65) in the MCOLN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MCOLN1 are known to be pathogenic (PMID: 11030752, 11317355, 37972748). This variant is present in population databases (rs755042147, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with mucolipidosis type IV (PMID: 18326692). ClinVar contains an entry for this variant (Variation ID: 208039). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.920delT (p.L307Pfs*65) alteration, located in exon 8 (coding exon 8) of the MCOLN1 gene, consists of a deletion of one nucleotide at position 920, causing a translational frameshift with a predicted alternate stop codon after 65 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.920delT allele has an overall frequency of 0.001% (4/282790) total alleles studied. The highest observed frequency was 0.003% (4/129108) of European (non-Finnish) alleles. This variant has been reported compound heterozygous in one individual with features consistent with Mucolipidosis IV (Goldin, 2008). Based on the available evidence, this alteration is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1. | Patterson K | American journal of ophthalmology | 2024 | PMID: 37972748 |
| Isolated ocular disease is associated with decreased mucolipin-1 channel conductance. | Goldin E | Investigative ophthalmology & visual science | 2008 | PMID: 18326692 |
| Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population. | Bargal R | Human mutation | 2001 | PMID: 11317355 |
| 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 rs755042147 ...
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.