rs754097561
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_020533.3(MCOLN1):c.1336G>A(p.Val446Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,838 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V446L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020533.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCOLN1 | NM_020533.3 | c.1336G>A | p.Val446Met | missense_variant | 11/14 | ENST00000264079.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCOLN1 | ENST00000264079.11 | c.1336G>A | p.Val446Met | missense_variant | 11/14 | 1 | NM_020533.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251458Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135908
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461838Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6AN XY: 727232
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Mucolipidosis type IV Pathogenic:4Uncertain:1
Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 446 of the MCOLN1 protein (p.Val446Met). This variant is present in population databases (rs754097561, gnomAD 0.007%). This missense change has been observed in individual(s) with MCOLN1-related conditions (PMID: 32860008). ClinVar contains an entry for this variant (Variation ID: 426811). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital | - | The MCOLN1 variant c.1336G>A p.(Val446Met) causes an amino acid change from Val to Met at position 446 in exon(s) no. 11 (of 14). According to HGMD Professional 2024.1, this variant has previously been described as disease causing for Mucolipidosis IV (PMID:31589614, 37644014, 36937954). ClinVar lists this variant (Interpretation: Conflicting interpretations of pathogenicity; Likely pathogenic (3), Uncertain significance (1); Variation ID: 426811). The reported patients in ClinVar are majority from Arab population suggesting possible founder effect. - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2017 | The V446M variant has not been published as a pathogenic variant, nor has itbeen reported as a benign variant to our knowledge. The V446M variant is not observed in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The V446M variant is a conservative amino acid substitution, which is not likely to impact secondaryprotein structure as these residues share similar properties. This substitution occurs at a position that isconserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. A missense variant at the same residue (V446L) has been reported in the HumanGene Mutation Database in association with mucolipidosis type IV (Stenson et al., 2014), supportingthe functional importance of this region of the protein. In summary, the V446M variant is likelypathogenic; however, the possibility that it is benign cannot be excluded. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at