rs121908374
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_020533.3(MCOLN1):c.1207C>T(p.Arg403Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R403H) has been classified as Uncertain significance.
Frequency
Consequence
NM_020533.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCOLN1 | NM_020533.3 | c.1207C>T | p.Arg403Cys | missense_variant | 10/14 | ENST00000264079.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCOLN1 | ENST00000264079.11 | c.1207C>T | p.Arg403Cys | missense_variant | 10/14 | 1 | NM_020533.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152142Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250946Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135694
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461210Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8AN XY: 726972
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74304
ClinVar
Submissions by phenotype
Mucolipidosis type IV Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 08, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 09, 2019 | Variant summary: MCOLN1 c.1207C>T (p.Arg403Cys) results in a non-conservative amino acid change located in the Polycystin cation channel, PKD1/PKD2 domain of 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 1.2e-05 in 250946 control chromosomes (gnomAD). c.1207C>T has been reported in the literature in individuals affected with Mucolipidosis Type 4 (Bach_2005, Goldin_2004). These data indicate that the variant may be associated with disease. Functional assays found the variant to significantly affect channel activity and subcellular localization (Dong_2008, Chen_2014). A ClinVar submission from a well established database, GeneReviews (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 11, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 403 of the MCOLN1 protein (p.Arg403Cys). This variant is present in population databases (rs121908374, gnomAD 0.003%). This missense change has been observed in individual(s) with mucolipidosis type IV (PMID: 15523648, 16287144, 35425852). 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: 5137). 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 expected to disrupt MCOLN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MCOLN1 function (PMID: 18794901, 25119295). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 26, 2023 | The MCOLN1 c.1207C>T (p.Arg403Cys) missense variant has been identified in a compound heterozygous state in two unrelated individuals and in a homozygous state in one individual with phenotypes consistent with mucolipidosis type IV (PMID: 15523648; 16287144; 36344503). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies conducted in non-human cell lines demonstrated that this variant significantly affects channel activity and subcellular localization (PMID: 18794901; 25119295). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant has been classified as likely pathogenic and pathogenic by at least three submitters in ClinVar. This variant was identified in a homozygous state. Based on the available evidence, the c.1207C>T (p.Arg403Cys) variant is classified as likely pathogenic for mucolipidosis type IV. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at