ClinVar Genomic variation as it relates to human health

NM_000492.3(CFTR):c.1040G>A(R347H) is classified as pathogenic in the context of cystic fibrosis and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1040G>A(R347H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

The variant was found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant is damaging to protein function(s) relevant to disease mechanism.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 347 of the CFTR protein (p.Arg347His). This variant is present in population databases (rs77932196, gnomAD 0.004%). This missense change has been observed in individuals with cystic fibrosis (CF) and is included in the American College of Medical Genetics (ACMG) panel of CF variants (PMID: 15371902, 23974870). ClinVar contains an entry for this variant (Variation ID: 7182). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. This variant disrupts the p.Arg347 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2344617, 7683952). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The CFTR c.1040G>A; p.Arg347His variant (rs77932196), is reported in the literature in multiple individuals affected with the pancreatic sufficient form of cystic fibrosis (Cremonesi 1992, Gallati 2009, Ooi 2012). The variant has also been reported in a compound heterozygous state in individuals with pancreatic insufficiency (de Gracia 2005, Izumikawa 2009) or congenital bilateral absence of vas deferens (Li 2012, Steiner 2011, Ravnik-Glavac 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 7182), and is found in the general population with an overall allele frequency of 0.003% (7/276828 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.1040G>C; p.Arg347Pro, c.1040G>T; p.Arg347Leu) have been reported in individuals with cystic fibrosis and are considered pathogenic (Audrezet 2004, Ooi 2012, Sosnay 2013, Van Goor 2014). Functional analyses of the variant protein shows a reduction of chloride transport activity (Anderson 1991, Clain 2001, Sheppard 1993, Smith 2001, Sosnay 2013, Van Goor 2014). The arginine at codon 347 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that the p.Arg347His variant is deleterious. Based on available information, this variant is considered to be moderately pathogenic. References: Anderson MP et al. Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science. 1991 Jul 12;253(5016):202-5. Audrezet MP et al. Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms. Hum Mutat. 2004 Apr;23(4):343-57. Clain J et al. Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function. J Biol Chem. 2001 Mar 23;276(12):9045-9. Cremonesi L et al. Four new mutations of the CFTR gene (541delC, R347H, R352Q, E585X) detected by DGGE analysis in Italian CF patients, associated with different clinical phenotypes. Hum Mutat. 1992 1(4):314-9. de Gracia J et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005 Jul;60(7):558-63. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 19(5):685-94. Izumikawa K et al. Unique mutations of the cystic fibrosis transmembrane conductance regulator gene of three cases of cystic fibrosis in Nagasaki, Japan. Intern Med. 2009;48(15):1327-31. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 Jul;11(4):316-23. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. Ravnik-Glavac M et al. Study of mutant and polyvariant mutant CFTR genes in patients with congenital absence of the vas deferens. Pflugers Arch. 2000;439(3 Suppl):R53-5. Sheppard DN et al. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature. 1993 Mar 11;362(6416):160-4. Smith SS et al. CFTR: covalent and noncovalent modification suggests a role for fixed charges in anion conduction. J Gen Physiol. 2001 Oct;118(4):407-31. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 13(1):29-36.

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD

The p.R347H pathogenic mutation (also known as c.1040G>A and 1172G>A), located in coding exon 8 of the CFTR gene, results from a G to A substitution at nucleotide position 1040. The arginine at codon 347 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in several individuals with CFTR or CFTR-related disorders and is included in the American College of Medical Genetics and Genomics (ACMG)'s list of recommended screening variants (Miller ME et al. J Obstet Gynaecol Can, 2018 Mar). In addition, this mutation has been detected in an individual with mild pulmonary disease and pancreatic sufficiency who carried p.F508del on the other allele (Cremonesi L. et al. Hum Mutat. 1992;1:314-319; Hojo S et al. Clin Genet. 1998;53:50-53). One functional study showed that this mutation results in reduced chloride channel activity but retains normal protein processing capabilities (Clain J et al. J Biol Chem. 2001;276(12):9045-9). Functional in vitro studies conclude that this mutation may be associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). Of note, this mutation has been observed as part of a complex allele with p.D979A (Hojo S et al. Clin Genet. 1998;53:50-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

CFTR: PM3:Very Strong, PM2, PM5, PP3

The CFTR c.1040G>A variant is predicted to result in the amino acid substitution p.Arg347His. This variant has been repeatedly documented to cause cystic fibrosis (see, for example, Cremonesi et al. 1992. PubMed ID: 1284538; Sosnay et al. 2013. PubMed ID: 23974870; cftr2.org). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.