rs1060502639
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004006.3(DMD):c.2665C>T(p.Arg889Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R889R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004006.3 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 |
---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.2665C>T | p.Arg889Ter | stop_gained | 21/79 | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.2665C>T | p.Arg889Ter | stop_gained | 21/79 | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 09, 2017 | The p.Arg889Ter variant has been previously identified in a large, multigenerational Australian pedigree wherein males were affected with Duchenne Muscular Dystrophy (DMD; Taylor 2007). While several women were tested, no males were available confirm this allele as causative. However, the p.Arg889Ter variant creates an early termination codon in exon 21 and is expected to result in a truncated or absent protein product. This variant is also absent from population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser, and several other truncating variants in exon 21 have been identified in DMD patients (selected reference: Hofstra 2004). Therefore, the p.Arg889Ter variant satisfies our criteria for classification as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 07, 2022 | - - |
Duchenne muscular dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Dec 16, 2022 | PVS1, PM2, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2023 | This sequence change creates a premature translational stop signal (p.Arg889*) in the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (PMID: 20098710, 21515508). ClinVar contains an entry for this variant (Variation ID: 409911). For these reasons, this variant has been classified as Pathogenic. - |
Qualitative or quantitative defects of dystrophin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 03, 2019 | Variant summary: DMD c.2665C>T (p.Arg889X) 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 183384 control chromosomes (gnomAD). c.2665C>T has been reported in the literature in multiple individuals affected with Dystrophinopathies (Mah_2011, Okubo_2017, Xu_2017, Taylor_2010, Zengui_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 19, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at