Submissions for variant NM_000492.4(CFTR):c.1253A>G (p.Asn418Ser)

gnomAD frequency: 0.00003  dbSNP: rs397508185

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811320	SCV000603035	uncertain significance	not provided	2020-12-09	criteria provided, single submitter	clinical testing	The CFTR c.1253A>G; p.Asn418Ser variant (rs397508185) is reported in the literature in individuals affected with cystic fibrosis, but its clinical significance was not determined (Angelicheva 1997, SickKids CFTR database). This variant is also reported in ClinVar (Variation ID: 53224), and is only observed on seven alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 418 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.173). Although some computational predictions suggest that the variant has a strong impact on splicing (Aissat 2013), minigene assays show only a modest effect (less than 10 percent increase in exon-skipping) (Pagani 2003). Due to limited information, the clinical significance of the p.Asn418Ser variant is uncertain at this time. References: Link to SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=217 Aissat A et al. Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. Hum Mutat. 2013; 34(6):873-81. Angelicheva D et al. Cystic fibrosis mutations and associated haplotypes in Bulgaria - a comparative population genetic study. Hum Genet. 1997; 99(4):513-20. Pagani F et al. Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. J Biol Chem. 2003; 278(29):26580-8.
Ambry Genetics	RCV001785467	SCV001170787	uncertain significance	Cystic fibrosis	2022-08-17	criteria provided, single submitter	clinical testing	The p.N418S variant (also known as c.1253A>G), located in coding exon 10 of the CFTR gene, results from an A to G substitution at nucleotide position 1253. The asparagine at codon 418 is replaced by serine, an amino acid with highly similar properties. This variant was reported in two unrelated cystic fibrosis cases with p.F508del, although phase information was not provided (Sava et al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids; [1994]). This amino acid position is poorly 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.
Genome-Nilou Lab	RCV001785467	SCV002027396	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490609	SCV002775909	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001785467	SCV003500575	uncertain significance	Cystic fibrosis	2022-03-07	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 418 of the CFTR protein (p.Asn418Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 53224). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 12732620, 23420618). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235011	SCV003934551	uncertain significance	not specified	2024-06-26	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1253A>G (p.Asn418Ser) results in a conservative amino acid change located in the Cystic fibrosis transmembrane conductance regulator, ATP-binding cassette domain 1 (IPR047082) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 247684 control chromosomes. c.1253A>G has been reported in the literature as an uninformative genotype (i.e. zygosity and/or second variant not specified) in individuals affected with Cystic Fibrosis (e.g. Angelicheva_1997, Raraigh_2022) and in the compound heterozygous state together with F508del in two unrelated patients in the SickKids CFTR database, however it was also noted that it was reported as a polymorphism by the contributors. These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication examined the effect of the variant on RNA splicing and found that it was associated with an increase in exon skipping, although this was only a mild effect when considering the level of skipping observed for the WT allele (e.g. Pagani_2003, Aissat_2013). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 31.30% of normal chloride channel conductance relative to wild type (example, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 23420618, 9099843, 12732620, 34782259, 38388235). ClinVar contains an entry for this variant (Variation ID: 53224). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc.	RCV001831725	SCV002080570	uncertain significance	CFTR-related disorder	2018-10-17	no assertion criteria provided	clinical testing