Submissions for variant NM_000492.4(CFTR):c.4433C>G (p.Thr1478Arg)

dbSNP: rs753173837

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001862220	SCV001184213	uncertain significance	Cystic fibrosis	2018-12-11	criteria provided, single submitter	clinical testing	The p.T1478R variant (also known as c.4433C>G), located in coding exon 27 of the CFTR gene, results from a C to G substitution at nucleotide position 4433. The threonine at codon 1478 is replaced by arginine, an amino acid with similar properties. This variant was identified in an infant with a positive cystic fibrosis newborn screen in conjunction with p.R553*; however, the phase was not provided (Prach L et al. J Mol Diagn, 2013 Sep;15:710-22). In addition, this variant was identified in the homozygous state in a male with congenital bilateral partial absence of the vas deferens (Yang X et al. Fertil. Steril., 2015 Nov;104:1268-75.e1-2). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862220	SCV002196660	likely pathogenic	Cystic fibrosis	2024-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 1478 of the CFTR protein (p.Thr1478Arg). This variant is present in population databases (rs753173837, gnomAD 0.006%). This missense change has been observed in individuals with congenital absence of the vas deferens (PMID: 26277102, 32777524). ClinVar contains an entry for this variant (Variation ID: 824887). 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 CFTR protein function with a positive predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331023	SCV004039267	uncertain significance	not specified	2023-08-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.4433C>G (p.Thr1478Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250814 control chromosomes in the gnomAD database, including 1 homozygotes suggesting a benign role for this variant. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4433C>G has been reported in the literature in individuals affected with congenital bilateral partial aplasia of the vas deferens (Yang_2015), congenital bilateral absence of the vas deferens (Pagin_2016), and CFTR-related metabolic syndrome (Prach_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32777524, 26900683, 23810505, 26277102). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001827205	SCV002075984	uncertain significance	CFTR-related disorder	2021-06-07	no assertion criteria provided	clinical testing