ClinVar Miner

Submissions for variant NM_016042.4(EXOSC3):c.312_313del (p.Gln105fs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002510386 SCV002819638 likely pathogenic Pontoneocerebellar hypoplasia 2022-12-02 criteria provided, single submitter clinical testing Variant summary: EXOSC3 c.312_313delTC (p.Gln105AlafsX19) 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 likely pathogenic by our laboratory and others have been reported in association with Pontocerebellar hypoplasia 1 in HGMD. The variant allele was found at a frequency of 2.2e-05 in 232178 control chromosomes. To our knowledge, no occurrence of c.312_313delTC in individuals affected with Pontocerebellar Hypoplasia, Type 1B and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003530273 SCV004301238 pathogenic Pontocerebellar hypoplasia type 1B 2023-07-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1878333). This variant has not been reported in the literature in individuals affected with EXOSC3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Gln105Alafs*19) in the EXOSC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXOSC3 are known to be pathogenic (PMID: 22544365, 23284067, 24524299).

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