ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1679G>A (p.Arg560Lys) (rs80055610)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000007576 SCV000071523 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007576 SCV000696864 pathogenic Cystic fibrosis 2017-06-13 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1679G>A (p.Arg560Lys) variant involves the alteration of a conserved nucleotide at the end of exon 12 and is located in P-loop containing nucleoside triphosphate hydrolase, AAA+ ATPase and/or ABC transporter 1 domain of the protein (InterPro). 4/5 in silico tools predict damaging outcome for this variant. In addition, 5/5 splice prediction tools predict that this variant weakens the canonical 5' splice donor site. This variant has been reported in several CF patients, majority of patients characterized to be pancreatic insufficient (Ferec_1992, Osika_1999, Scotet_2003, Sosnay_2013) and is absent in 118816 control chromosomes from ExAC. Functional analysis shows that this variant leads to defective chloride channel and/or CFTR processing (Sosnay_2013). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Other missense changes at the same residue, namely p.Arg560Gly, p.Arg560Ser, and p.Arg560Thr have been reported to associate with CF, indicating Arg560 is a mutational hot-spot. Taken together, this variant is classified as pathogenic.
Counsyl RCV000007576 SCV000799371 likely pathogenic Cystic fibrosis 2018-04-16 criteria provided, single submitter clinical testing
CFTR-France RCV000007576 SCV001169390 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Invitae RCV000007576 SCV001587480 pathogenic Cystic fibrosis 2020-07-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 560 of the CFTR protein (p.Arg560Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 12 of the CFTR coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with cystic fibrosis (PMID: 23974870). ClinVar contains an entry for this variant (Variation ID: 7156). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg560 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15371902, 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007576 SCV000027777 pathogenic Cystic fibrosis 1992-06-01 no assertion criteria provided literature only

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