ClinVar Miner

Submissions for variant NM_004990.4(MARS1):c.1091+2dup (rs754216322)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493973 SCV000582711 uncertain significance not specified 2017-05-18 criteria provided, single submitter clinical testing The c.1091+2dupT variant in the MARS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 9. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1091+2dupT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1091+2dupT as a variant of uncertain significance.
Invitae RCV000652563 SCV000774433 uncertain significance Interstitial lung and liver disease; Charcot-Marie-Tooth disease, axonal, type 2u 2017-08-14 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the MARS gene. It does not directly change the encoded amino acid sequence of the MARS protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs754216322, ExAC 0.006%). This variant has not been reported in the literature in individuals with MARS-related disease. ClinVar contains an entry for this variant (Variation ID: 430002). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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