ClinVar Miner

Submissions for variant NM_025103.4(IFT74):c.120+2dup

gnomAD frequency: 0.00048  dbSNP: rs551515830
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001857887 SCV002149015 uncertain significance not provided 2022-10-05 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the IFT74 gene. It does not directly change the encoded amino acid sequence of the IFT74 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs551515830, gnomAD 0.07%). This variant has been observed in individual(s) with clinical features of IFT74-related conditions (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446698). Variants that disrupt 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. 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.
Dan Cohn Lab, University Of California Los Angeles RCV000515942 SCV000612135 uncertain significance Short-rib thoracic dysplasia 6 with or without polydactyly 2017-06-01 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000515942 SCV001479712 likely pathogenic Short-rib thoracic dysplasia 6 with or without polydactyly no assertion criteria provided research
PreventionGenetics, part of Exact Sciences RCV003962425 SCV004778712 uncertain significance IFT74-related disorder 2024-08-20 no assertion criteria provided clinical testing The IFT74 c.120+2dupT variant is predicted to result in a duplication affecting a canonical splice site. This variant is predicted to impact the consensus donor site splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), although it does not eliminate the consensus GT donor site sequence at the junction of exon 2 and intron 2 (GT>GTT). This variant has been identified with another variant of IFT74 in a patient with Bardet-Biedl syndrome, but the phase of the variants was not established (Table S1, Schlottmann et al. 2023. PubMed ID: 37217489). This variant has also been identified in the heterozygous state in one patient with an autosomal recessive skeletal ciliopathy known as short rib-polydactyly syndrome type II (Table S3, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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