ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1251C>A (p.Asn417Lys) (rs4727853)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Clinical Services Laboratory,Illumina RCV001095146 SCV000466511 likely benign CFTR-related disorders 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.
Invitae RCV000366455 SCV000562317 benign Cystic fibrosis 2020-11-06 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.
Nilou-Genome Lab RCV000366455 SCV001822043 likely benign Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing

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