rs121908371
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_020533.3(MCOLN1):c.964C>T(p.Arg322Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,094 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R322R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_020533.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCOLN1 | NM_020533.3 | c.964C>T | p.Arg322Ter | stop_gained | 8/14 | ENST00000264079.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCOLN1 | ENST00000264079.11 | c.964C>T | p.Arg322Ter | stop_gained | 8/14 | 1 | NM_020533.3 | P1 | |
MCOLN1 | ENST00000394321.9 | n.1279C>T | non_coding_transcript_exon_variant | 7/13 | 2 | ||||
MCOLN1 | ENST00000595860.5 | n.30C>T | non_coding_transcript_exon_variant | 1/4 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461860Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727234
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Mucolipidosis type IV Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Oct 22, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Arg322*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with mucolipidosis type IV (PMID: 10973263, 11317355). ClinVar contains an entry for this variant (Variation ID: 5133). 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 24, 2019 | Variant summary: MCOLN1 c.964C>T (p.Arg322X) 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. The variant was absent in 251318 control chromosomes (gnomAD). c.964C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Mucolipidosis Type 4 (Bargal_2000, Bargal_2001). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 02, 2022 | The c.964C>T (p.R322*) alteration, located in exon 8 (coding exon 8) of the MCOLN1 gene, consists of a C to T substitution at nucleotide position 964. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 322. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in the homozygous and compound heterozygous states in individuals with mucolipidosis IV (Bargal, 2000; Bargal, 2001; Ziats, 2020). Based on the available evidence, this alteration is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2016 | The R322X variant has been reported previously in association with mucolipidosis type IV and has also been reported as R321X due to the use of alternative nomenclature (Bargal et al., 2000; Bargal et al., 2001). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Given the available evidence, we interpret R322X as a pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at