ClinVar Miner

Submissions for variant NM_002225.5(IVD):c.870dup (p.Pro291fs) (rs759159766)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000555769 SCV000631892 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2017-03-21 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 8 of the IVD mRNA (c.879dupG), causing a frameshift at codon 294. This creates a premature translational stop signal (p.Pro294Alafs*38) and is expected to result in an absent or disrupted protein product. While this variant is present in population databases (rs759159766), the frequency information is unreliable because metric data are not available for quality assessment. This particular variant has been identified in combination with another IVD variant in the fibroblasts from an individual affected with isovaleric acidemia (PMID: 10677295). This variant is also known as iG870 in the literature. RNA analyses in patient fibroblasts have shown that this variant results in aberrant gene products with reduced stability. In addition to the anticipated products containing the guanine insertion in exon 8, this variant is also associated with splicing defects involving exon 8 skipping which is anticipated to cause an out-of-frame loss-of-function deletion in the encoded protein. Consistently, expression of the recombinant mutant allele in CHO cells supports that this variant causes aberrant splicing (PMID: 10677295). In summary, this is a rare variant which results in loss-of-function changes by creating a premature translational stop signal and causing an out-of-frame exon 8 skipping event. Loss of function variants in IVD are known to be pathogenic (PMID: 23587913, 10677295). For these reasons, this variant has been classified as Pathogenic.

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