Submissions for variant NM_020800.3(IFT80):c.721G>C (p.Gly241Arg)

gnomAD frequency: 0.00043  dbSNP: rs138004478

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474945	SCV000544760	pathogenic	Jeune thoracic dystrophy	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 241 of the IFT80 protein (p.Gly241Arg). This variant is present in population databases (rs138004478, gnomAD 0.1%). This missense change has been observed in individuals with short-rib thoracic dysplasia (PMID: 19648123, 29068549, 30266093). ClinVar contains an entry for this variant (Variation ID: 406218). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt IFT80 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003103777	SCV000604009	likely pathogenic	Asphyxiating thoracic dystrophy 2	2023-06-01	criteria provided, single submitter	clinical testing	The IFT80 c.721G>C; p.Gly241Arg variant (rs138004478) is reported in the literature in the homozygous or compound heterozygous state in individuals affected with short-rib thoracic dysplasia II, asphyxiating thoracic dystrophy, or Jeune-Verma-Naumoff dysplasia (Cavalcanti 2011, Normand 2018, Zhang 2018). This variant is also reported in ClinVar (Variation ID: 406218), and is found in the African/African-American population with an allele frequency of 0.12% (30/24974 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.628). Based on available information, this variant is considered to be likely pathogenic. References: Cavalcanti D et al. Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum. J Med Genet. 2011; 48(2):88-92. PMID: 19648123. Normand EA et al. Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder. Genome Med. 2018 Sep 28;10(1):74. PMID: 30266093. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549.
Dan Cohn Lab, University Of California Los Angeles	RCV000474945	SCV000612067	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
Dan Cohn Lab, University Of California Los Angeles	RCV000516104	SCV000612070	pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly	2017-06-01	no assertion criteria provided	research
Eurofins Ntd Llc (ga)	RCV000727148	SCV000706155	uncertain significance	not provided	2017-03-02	flagged submission	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV000474945	SCV001479583	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000516104	SCV001479586	likely pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004758018	SCV005356203	pathogenic	IFT80-related disorder	2024-07-08	no assertion criteria provided	clinical testing	The IFT80 c.721G>C variant is predicted to result in the amino acid substitution p.Gly241Arg. This variant was reported in the homozygous state in multiple individuals with short-rib thoracic dysplasia (Cavalcanti et al. 2011. PubMed ID: 19648123; Zhang et al. 2017. PubMed ID: 29068549; Normand et al. 2018. PubMed ID: 30266093). This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.