ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000173697 SCV000224841 benign not specified 2015-03-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000366455 SCV000466511 likely benign Cystic fibrosis 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000366455 SCV000562317 benign Cystic fibrosis 2018-01-05 criteria provided, single submitter clinical testing

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