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

gnomAD frequency: 0.00048  dbSNP: rs551515830

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	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.
PreventionGenetics, part of Exact Sciences	RCV003962425	SCV004778712	uncertain significance	IFT74-related condition	2024-02-21	criteria provided, single submitter	clinical testing	The IFT74 c.120+2dupT variant is predicted to result in an intronic duplication. This variant is predicted to impact the consensus donor site based on available splicing prediction programs (Alamut Visual Plus v1.6.1), 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 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.
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