Submissions for variant NM_015662.3(IFT172):c.1445T>G (p.Val482Gly)

gnomAD frequency: 0.00006  dbSNP: rs61740250

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001251461	SCV001427160	likely pathogenic	Short-rib thoracic dysplasia 10 with or without polydactyly	2018-07-27	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_015662.1(IFT172):c.1445T>G, has been identified in exon 15 of 48 of the IFT172 gene. The variant is predicted to result in a major amino acid change from valine to glycine at position 482 of the protein (NP_056477.1(IFT172):p.(Val482Gly)). The valine at this position has low conservation (100 vertebrates, UCSC), and is not located within a well established functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.009% (25 heterozygotes and 0 homozygotes), but has not been previously reported in clinical cases. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with short-rib thoracic dysplasia 10 with or without polydactyly. Based on current information, this variant has been classified as LIKELY PATHOGENIC. NB: This variant has been reclassified to likely pathogenic due to confirmation of autosomal recessive inheritance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001314402	SCV001504935	uncertain significance	Short-rib thoracic dysplasia 10 with or without polydactyly; Retinitis pigmentosa 71	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 482 of the IFT172 protein (p.Val482Gly). This variant is present in population databases (rs61740250, gnomAD 0.02%). This missense change has been observed in individual(s) with IFT172-related conditions (PMID: 32939031; Invitae). ClinVar contains an entry for this variant (Variation ID: 975059). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	RCV004548104	SCV004116680	uncertain significance	IFT172-related disorder	2023-09-22	criteria provided, single submitter	clinical testing	The IFT172 c.1445T>G variant is predicted to result in the amino acid substitution p.Val482Gly. This variant was reported in the compound heterozygous state in an individual with clinical features of Senior-Loken syndrome (Table S2, Jayasinghe et al. 2021. PubMed ID: 32939031). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-27695196-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Fulgent Genetics, Fulgent Genetics	RCV005014307	SCV005651464	uncertain significance	Short-rib thoracic dysplasia 10 with or without polydactyly; Retinitis pigmentosa 71; Bardet-Biedl syndrome 20	2024-06-18	criteria provided, single submitter	clinical testing