Submissions for variant NM_015662.3(IFT172):c.786-2A>T

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471620	SCV002769025	uncertain significance	Retinitis pigmentosa 71	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 71 (MIM#616394) and short-rib thoracic dysplasia 10 with or without polydactyly (MIM#615630). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002571459	SCV003258055	likely pathogenic	Short-rib thoracic dysplasia 10 with or without polydactyly; Retinitis pigmentosa 71	2024-05-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the IFT172 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IFT172 are known to be pathogenic (PMID: 24140113). This variant is present in population databases (rs757253624, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with IFT172-related conditions. ClinVar contains an entry for this variant (Variation ID: 1805202). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005025838	SCV005651492	likely pathogenic	Short-rib thoracic dysplasia 10 with or without polydactyly; Retinitis pigmentosa 71; Bardet-Biedl syndrome 20	2024-06-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004738582	SCV005359770	likely pathogenic	IFT172-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The IFT172 c.786-2A>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in IFT172 are expected to be pathogenic. This variant is interpreted as likely pathogenic.