Submissions for variant NM_015662.3(IFT172):c.2765dup (p.Tyr922Ter)

gnomAD frequency: 0.00001  dbSNP: rs750338419

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810508	SCV000950714	pathogenic	Short-rib thoracic dysplasia 10 with or without polydactyly; Retinitis pigmentosa 71	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr922*) in the IFT172 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IFT172 are known to be pathogenic (PMID: 24140113). This variant is present in population databases (rs750338419, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with short-rib polydactyly syndromes type 2 (SRPS type 2) (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446697). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002476034	SCV001752580	pathogenic	Short-rib thoracic dysplasia 10 with or without polydactyly; Retinitis pigmentosa 71; Bardet-Biedl syndrome 20	2024-04-27	criteria provided, single submitter	clinical testing
GeneDx	RCV003128621	SCV003805919	likely pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing	Identified heterozygous in a patient with short rib-polydactyly syndrome via whole exome sequencing in the published literature (Zhang et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24140113, 29068549)
Dan Cohn Lab, University Of California Los Angeles	RCV000515844	SCV000612134	likely pathogenic	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	RCV000515844	SCV001479711	likely pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004551657	SCV004789641	pathogenic	IFT172-related disorder	2024-02-08	no assertion criteria provided	clinical testing	The IFT172 c.2765dupA variant is predicted to result in premature protein termination (p.Tyr922*). This variant has been reported in an individual with short rib-polydactyly syndrome type 2; however, a second variant in IFT172 was not identified and the patient was reported to harbor several other variants in different genes (Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in IFT172 are expected to be pathogenic, and this variant is classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/446697/). We interpret c.2765dup (p.Tyr922*) as pathogenic.