ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.742A>G (p.Arg248Gly)

dbSNP: rs1554380515
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671274 SCV000796233 uncertain significance Cystic fibrosis 2017-12-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002407 SCV001160338 likely pathogenic not specified 2019-02-19 criteria provided, single submitter clinical testing The CFTR c.742A>G; p.Arg248Gly variant is reported in the literature in three siblings affected with pancreatitis or congenital absence of the vas deferens (Villalona 2017). In all three affected siblings, this variant was observed in trans to a second pathogenic variant (Villalona 2017). The p.Arg248Gly variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 248 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Another variant at the same codon (p.Arg248Thr) has been reported in individuals with CFTR-related disorders in trans to a pathogenic variant (Polizzi 2011, SickKids CFTR Mutation Database). Additionally, the c.742A>G; p.Arg248Gly occurs in the penultimate nucleotide of an exon, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Although this variant is unlikely to be causative for classic cystic fibrosis, based on available information, we consider this variant to be likely pathogenic for other CFTR-related disorders. References: SickKids CFTR Mutation Database: http://www.genet.sickkids.on.ca/cftr/Home.html Polizzi A et al. Genotype-phenotype correlation in cystic fibrosis patients bearing [H939R;H949L] allele. Genet Mol Biol. 2011 Jul;34(3):416-20. Villalona S et al. R248G cystic fibrosis transmembrane conductance regulator mutation in three siblings presenting with recurrent acute pancreatitis and reproductive issues: a case series. J Med Case Rep. 2017 Feb 15;11(1):42.
Mayo Clinic Laboratories, Mayo Clinic RCV001509315 SCV001715949 uncertain significance not provided 2021-03-10 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000671274 SCV001822019 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000671274 SCV004274210 pathogenic Cystic fibrosis 2023-07-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 248 of the CFTR protein (p.Arg248Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CFTR-related conditions and/or clinical features of CFTR-related conditions (PMID: 28196530). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555450). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000671274 SCV001454030 likely pathogenic Cystic fibrosis 2020-09-16 no assertion criteria provided clinical testing

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