ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.944T>C (p.Phe315Ser) (rs760319837)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000554519 SCV000625757 uncertain significance Cystic fibrosis 2019-04-28 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 315 of the CFTR protein (p.Phe315Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs760319837, ExAC 0.2%). This variant has been reported in an individual affected with CFTR-related metabolic syndrome (PMID: 23810505). ClinVar contains an entry for this variant (Variation ID: 455784). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV000855642 SCV000697059 uncertain significance not specified 2019-07-26 criteria provided, single submitter clinical testing Variant summary: CFTR c.944T>C (p.Phe315Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 282672 control chromosomes the gnomAD database, exclusively observed within the Latino subpopulation at a frequency of 0.0012. This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0012 vs 0.013), allowing no conclusion about variant significance. c.944T>C has been reported in the literature in one newborn of Hispanic ethnicity with CFTR-related metabolic syndrome (Prach_2013). This report does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589384 SCV000856956 uncertain significance not provided 2017-09-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000589384 SCV000883577 uncertain significance not provided 2017-12-13 criteria provided, single submitter clinical testing The CFTR c.944T>C; p.Phe315Ser variant is reported in the medical literature in one individual with CFTR-related metabolic disorder (Prach 2013). The variant is listed in the dbSNP variant database (rs760319837) and in the Genome Aggregation Database in 45/277018 alleles, but is not listed in the ClinVar database. The phenylalanine at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, there is insufficient evidence to classify this variant with certainty. References: Prach L et al. Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California. J Mol Diagn. 2013 Sep;15(5):710-22.

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