ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2908G>C (p.Gly970Arg)

dbSNP: rs397508453
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000056374 SCV000071503 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000056374 SCV000696933 pathogenic Cystic fibrosis 2017-06-13 criteria provided, single submitter clinical testing Variant summary: The CFTR c.2908G>C (p.Gly970Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, located in the cytoplasmic loop 3 of the CFTR cytoplasmic domain. This is confirmed by multiple functional studies showing that the G970R mutant CFTRs yielded fully mature protein (170 kDa) and the glycosylated protein reached plasma membrane but had lower level of PKA- and ATP-dependent channel activity with lower channel mean open probability and decreased Iodide efflux in Chinese hamster ovary (CHO) cells (Seibert_JBC_1996). Another study showed that the HCO3-/Cl- transport ratio was severely impaired and in line with other PI-specific mutations. Functional In vitro analysis from another paper reported <10% chloride transport when expressed in HeLa and Fischer rat thyroid (FRT) (Sosnay_2013). The variant of interest has not been found in a large, broad control population, ExAC in 121162 control chromosomes. This variant was found in multiple CF patients with mean sweat chloride conc 60mM (Sosnay_Nature Genetics_2013). In addition, one reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
CFTR-France RCV000056374 SCV001169518 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Labcorp Genetics (formerly Invitae), Labcorp RCV000056374 SCV003440104 pathogenic Cystic fibrosis 2022-03-02 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 53590). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 970 of the CFTR protein (p.Gly970Arg). This variant also falls at the last nucleotide of exon 17, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cystic fibrosis (PMID: 23974870, 33278322). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 30851139, 33278322). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV001826650 SCV002083559 pathogenic CFTR-related disorder 2017-03-17 no assertion criteria provided clinical testing

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