Submissions for variant NM_000492.4(CFTR):c.4333G>A (p.Asp1445Asn)

gnomAD frequency: 0.00074  dbSNP: rs148783445

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047128	SCV000075141	likely benign	Cystic fibrosis	2021-12-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586730	SCV000601121	uncertain significance	not provided	2021-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506986	SCV000697023	uncertain significance	not specified	2022-05-18	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.4333G>A (p.Asp1445Asn) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 251444 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00034 vs 0.013), allowing no conclusion about variant significance. c.4333G>A has been reported in the literature in individuals affected with or suspected to exhibit symptoms of Cystic Fibrosis and Cystic Fibrosis related disorders (examples- Claustres_2000, Schrijver_2005, Trujilliano_2015, Zeigler_2020, da Silva Filho_2020). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The variant has also been reported in compound heterozygosity with a well-known pathogenic mutation (CFTR F508del) in at least one infant who had a normal sweat chloride test (Castellani_2016). In addition, the variant has been reported in individuals affected with pancreatitis (Keiles_2006, Masson_2013), sarcoidosis (Makrythanasis_2010), and congenital unilateral absence of vas deferens (CUAVD; Mieusset_2019), but without strong evidence for causality. At least one publication reports experimental evidence indicating that the variant does not disrupt interactions with AMPK in a yeast-based assay (Hallows_2000), however the clinical significance of this finding is not clear. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=9) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Eurofins NTD LLC (GA)	RCV000586730	SCV000700517	uncertain significance	not provided	2018-04-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000586730	SCV000885178	uncertain significance	not provided	2020-12-10	criteria provided, single submitter	clinical testing	The CFTR c.4333G>A; p.Asp1445Asn variant (rs148783445) is reported in the medical literature in individuals affected with cystic fibrosis or other CFTR-related disorders, but without clear association with disease (Castellani 2017, Claustres 2000, Keiles 2006, Masson 2013, Mieusset 2020, Picca 2010, Schrijver 2005, Zeiger 2020). This variant is reported in ClinVar (Variation ID: 53941), and is found in the general population with an overall allele frequency of 0.04% (106/282286 alleles) in the Genome Aggregation Database. The aspartic acid at codon 1445 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.537). However, given the lack of specific clinical and functional data, the significance of the p.Asp1445Asn variant is uncertain at this time. References: Castellani C et al. Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis. Arch Dis Child. 2017 Jul;102(7):644-646. Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-56. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. Masson E et al. A Conservative Assessment of the Major Genetic Causes of Idiopathic Chronic Pancreatitis: Data from a Comprehensive Analysis of PRSS1, SPINK1, CTRC and CFTR Genes in 253 Young French Patients. PLoS One. 2013; 8(8): e73522. Mieusset R et al. Male partners of infertile couples with congenital unilateral absence of the vas deferens are mainly non-azoospermic. Andrology. 2020 May;8(3):645-653. Picci L et al. A 10-year large-scale cystic fibrosis carrier screening in the Italian population. J Cyst Fibros. 2010 Jan;9(1):29-35. Schrijver I et al. Diagnostic Testing by CFTR Gene Mutation Analysis in a Large Group of Hispanics. J Mol Diagn. 2005 May; 7(2): 289–299. Zeiger AM et al. Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico. Pediatr Pulmonol. 2020 Feb;55(2):533-540.
Mendelics	RCV000047128	SCV000886359	uncertain significance	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586730	SCV001155244	uncertain significance	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000047128	SCV001167307	uncertain significance	Cystic fibrosis	2019-11-22	criteria provided, single submitter	clinical testing	This CFTR variant has been previously identified in patients with features of cystic fibrosis, but also in one infant with a normal sweat chloride concentration. The clinical significance of this variant is classified as uncertain by multiple submitters in ClinVar. CFTR c.4333G>A (rs148783445) has been identified in a large population datasets and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the African subpopulation (gnomAD: 50/24958 alleles; 0.02%, no homozygotes). Of three bioinformatics tools queried, two predict that the substitution would be possibly damaging, while one predicts that it would be tolerated. The aspartic acid residue at this position is conserved across many, but not all of the species assessed. We consider the clinical significance of c.4333G>A to be uncertain at this time.
Ambry Genetics	RCV001022311	SCV001184030	uncertain significance	Inborn genetic diseases	2020-10-13	criteria provided, single submitter	clinical testing	The p.D1445N variant (also known as c.4333G>A), located in coding exon 27 of the CFTR gene, results from a G to A substitution at nucleotide position 4333. The aspartic acid at codon 1445 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in individuals with cystic fibrosis; however, specific phenotype and genotype information were not provided (Schrijver I et al. J Mol Diagn, 2005 May;7:289-99; Zeiger AM et al. Pediatr Pulmonol, 2020 02;55:533-540). In an individual with an abnormal newborn screen, this variant was detected in conjunction with p.F508del (phase unknown) with a sweat chloride level of 20 mmol/L (Castellani C et al. Arch Dis Child, 2017 07;102:644-646). This variant was detected in an individual with idiopathic chronic pancreatitis with a second CFTR variant; phase information was not provided (Masson E et al. PLoS One, 2013 Aug;8:e73522). In one study, p.D1445N had no effect on the interaction strength between the CFTR COOH-terminal tail and AMP-activated protein kinase and did not appear important for binding (Hallows KR et al. J. Clin. Invest., 2000 Jun;105:1711-21). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital	RCV000586730	SCV001450106	likely pathogenic	not provided	2014-07-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000586730	SCV001983814	uncertain significance	not provided	2021-10-12	criteria provided, single submitter	clinical testing	Observed in individuals with cystic fibrosis and other CFTR-related disorders, without a second CFTR variant reported (Claustres 2000, Schrijver 2005, Keiles 2006, Trujillano 2015); Observed with a pathogenic variant, phase unknown, in an infant without cystic fibrosis and a normal sweat chloride result (Castellani 2017); Published functional studies are inconclusive: normal interaction with AMPK, the clinical significance of which is unknown (Hallows 2000); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 15858154, 17003641, 10923036, 26436105, 22995991, 23951356, 25735457, 19897426, 26847993, 10862786, 32357917, 26755536, 20722470, 31665830)
Natera, Inc.	RCV000047128	SCV001460123	uncertain significance	Cystic fibrosis	2017-05-17	no assertion criteria provided	clinical testing