ClinVar Miner

Submissions for variant NM_016247.4(IMPG2):c.3423-7_3423-4del

dbSNP: rs534452999
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000175212 SCV000226657 uncertain significance not provided 2015-04-28 criteria provided, single submitter clinical testing
Invitae RCV000175212 SCV001205477 pathogenic not provided 2023-12-11 criteria provided, single submitter clinical testing This sequence change falls in intron 16 of the IMPG2 gene. It does not directly change the encoded amino acid sequence of the IMPG2 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs534452999, gnomAD 0.02%). This variant has been observed in individual(s) with autosomal recessive retinitis pigmentosa (PMID: 22334370, 24876279; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.3423-8_c.3423-5del. ClinVar contains an entry for this variant (Variation ID: 194768). Studies have shown that this variant results in activation of a cryptic splice site and introduces a new termination codon (PMID: 24876279). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074812 SCV001240410 pathogenic Retinal dystrophy 2019-07-11 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV002288779 SCV002580003 likely pathogenic Retinitis pigmentosa 56 2022-06-02 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV002288779 SCV003922103 likely pathogenic Retinitis pigmentosa 56 2023-05-02 criteria provided, single submitter curation The heterozygous c.3423-7_3423-4del variant in IMPG2 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (hg19, chr3:g.100986245_100986485del), in two siblings with retinal degeneration. Familial exome analysis revealed that this variant was in trans with a likely pathogenic variant (hg19, chr3:g.100986245_100986485del). The heterozygous c.3423-7_3423-4del has been previously reported in two siblings with retinitis pigmentosa 56 and segregated with disease in this family (PMID: 22334370, 24876279), but has been identified in 0.03% (19/68042) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs534452999). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 194768) with conflicting interpretations of pathogenicity. The two affected siblings previously reported (PMID: 22334370, 24876279) were compound heterozygotes who carried a reported pathogenic variant in trans (ClinVar Variation ID: 845633), which increases the likelihood that the c.3423-7_3423-4del variant is pathogenic. RT-PCR analysis performed on affected tissue showed evidence of altered splicing, with use of alternate upstream splice acceptor site in intron 16, resulting in the inclusion of 80 additional nucleotides to the IMPG2 mRNA, frameshift, and premature truncation (PMID: 24876279). This variant is located in the 3’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive retinitis pigmentosa 56. ACMG/AMP Criteria applied: PS3_Moderate, PM3_Strong, PP1 (Richards 2015).

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