rs797044823
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_020533.3(MCOLN1):c.1453_1463dupGGCCGCAGCAG(p.Ser488ArgfsTer96) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000397 in 1,613,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000042 ( 0 hom. )
Consequence
MCOLN1
NM_020533.3 frameshift
NM_020533.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.60
Genes affected
MCOLN1 (HGNC:13356): (mucolipin TRP cation channel 1) This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-7530370-G-GCGCAGCAGGGC is Pathogenic according to our data. Variant chr19-7530370-G-GCGCAGCAGGGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
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GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152232Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461556Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35AN XY: 727084
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74368
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucolipidosis type IV Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 29, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change results in a frameshift in the MCOLN1 gene (p.Ser488Argfs*96). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 93 amino acid(s) of the MCOLN1 protein and extend the protein by 2 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with MCOLN1-related conditions (PMID: 11317355, 12182165). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208029). This variant disrupts a region of the MCOLN1 protein in which other variant(s) (p.Ala539Profs*41) have been determined to be pathogenic (PMID: 18326692). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 22, 2016 | Variant summary: The MCOLN1 c.1453_1463dup11 (p.Ser488Argfs) variant was classified as pathogenic. It is a frameshift mutation predicted to alter the 580 amino acid long MCOLN1 protein starting at position 488 and resulting in a STOP codon 96 amino acids downstream. The variant likely results in a loss of protein function due to nonsense mediated decay or due to production of an abnormal protein. Mutation taster predicts the variant to be disease causing. The variant is absent from the general population, while it was reported in Mucolipidosis type IV patients indicating pathogenicity. Databases list the variant with a classification of pathogenic. Considering all evidence, the variant was classified as pathogenic. - |
Mucolipidosis type IV;C2749050:Lisch epithelial corneal dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at