rs1554160638
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000255.4(MMUT):c.670G>T(p.Glu224Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,244 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000255.4 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 |
---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.670G>T | p.Glu224Ter | stop_gained | 3/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.670G>T | p.Glu224Ter | stop_gained | 3/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.670G>T | p.Glu224Ter | stop_gained | 3/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460244Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 726478
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2019 | The E224X variant has been reported previously in an individual with mut0 MMA who also had a second nonsense variant identified in the MUT gene (Worgan et al., 2006). The E224X variant is not observed in large population cohorts (Lek et al., 2016). This E224X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret E224X as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 552718). This premature translational stop signal has been observed in individual(s) with methylmalonic aciduria (PMID: 16281286). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu224*) in the MUT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 22, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 05, 2017 | - - |
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 10, 2021 | - - |
Methylmalonic acidemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 18, 2021 | Variant summary: MUT c.670G>T (p.Glu224X) 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 was absent in 250444 control chromosomes. c.670G>T has been reported in the literature as a compound heterozygous genotype with another loss of function variant in at-least one individual affected with Methylmalonic Acidemia and this individual has been subsequently cited and comprehensively analyzed in numerous subsequent studies (example, Worgan_2006, O'Shea_2012, Manoli_2016, Harrington_2016, Hauser_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at