Submissions for variant NM_000492.4(CFTR):c.1251C>A (p.Asn417Lys)

dbSNP: rs4727853

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173697	SCV000224841	benign	not specified	2015-03-21	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224343	SCV000281114	benign	not provided	2015-12-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095146	SCV000466511	likely benign	CFTR-related disorder	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000366455	SCV000562317	benign	Cystic fibrosis	2024-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000224343	SCV000696832	uncertain significance	not provided	2017-08-22	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1251C>A (p.Asn417Lys) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 5925/206340 control chromosomes (gnomAD) at a frequency of 0.02871, which is approximately 1.5 times the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603), suggesting this variant is likely a benign polymorphism. However, gnomAD notes that the variant is located in a "segmental duplication region, failed random forests filters, and has an inbreeding coefficient of < -0.03." ExAC, 1790/94952 (frequency: 0.01885) notes that this variant is only covered in 47476 individuals (adjusted allele number = 94952), which is fewer than 80% of the individuals in ExAC, indicating a potentially low-quality site. In addition, each control database, gnomAD and ExAC, show significantly different allele frequencies in each of the subpopulations, making interpretation of the data difficult. Additionally, the relatively high allele frequencies reported by ExAC and gnomAD would be expected to result in homozygous individuals in the population if the allele is benign; however, neither database reports any homozygotes, despite allele frequencies as high as 9-12% in some subpopulations. This may be due to linkage to a nearby pathogenic variant, such as deltaF508, where homozygosity of the variant of interest results in homozygosity of the pathogenic allele, leading to a absence of homozygotes for the variant in the general population. The variant has been reported in the literature without strong evidence for or against causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign or benign. Taken together, this variant is classified as a "Variant of Uncertain Significance - Possibly Benign," until additional information becomes available such as higher quality control data and/or functional studies.
Genome-Nilou Lab	RCV000366455	SCV001822043	likely benign	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000224343	SCV002009135	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224343	SCV002046111	benign	not provided	2020-09-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000366455	SCV002669577	likely benign	Cystic fibrosis	2019-09-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Neuberg Centre For Genomic Medicine, NCGM	RCV000366455	SCV004100915	uncertain significance	Cystic fibrosis		criteria provided, single submitter	clinical testing	The missense variant p.N417K in CFTR (NM_000492.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. Although the variant is present at 0.5826% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.N417K variant is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between asparagine and lysine. The p.N417K missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The nucleotide c.1251 in CFTR is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.