ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1841A>G (p.Asp614Gly) (rs201124247)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000577786 SCV000696877 pathogenic Cystic fibrosis 2021-04-06 criteria provided, single submitter clinical testing Variant summary: CFTR c.1841A>G (p.Asp614Gly) results in a non-conservative amino acid change located in the ABC transporter-like (IPR003439) and AAA+ ATPase domains (IPR003593) 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 3.1e-05 in 229320 control chromosomes. c.1841A>G has been reported in compound heterozygosity with another pathogenic variant in multiple individuals affected with CF and CBAVD in the literature (e.g. Wilschanski_1995, Grangeia_2004, Lucarelli_2015, Pereira_2019, McCague_2019). Many of these patients have been reported with borderline sweat chloride levels and/or as pancreatic-sufficient, suggesting that the variant may be associated with a milder non-classical CF phenotype. The variant was also detected in compound heterozygosity with the common severe disease causing variant CFTR p.Phe508del in three siblings diagnosed in adulthood with atypical CF phenotypes of varying degrees of severity, leading the authors to conclude that this variant may be a "mild" CF mutation (e.g. Castaldo_2006). Collectively, these data indicate that the variant is likely to be associated with disease. Several publications report in-vitro experimental evidence evaluating an impact on protein function, reporting that the variant reduced CFTR processing in multiple cell lines (e.g. Pasyk_1998 Vankeerberghen_1998, Sosnay_2013). The variant was also observed to at least partially reduce measured current activity and alter the dynamics of channel gate opening and closing (Pasyk_1998, Sosnay_2013). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as pathogenic and one laboratory cited the variant as uncertain significance. The CFTR2 database reports the variant as having varying consequences as some individuals with this variant and another pathogenic variant have CF, while others do not, indicating that clinical criteria alone should be used in the diagnosis of patients with this variant. Based on the evidence outlined above, the variant was classified as pathogenic for non-classic CF.
Mendelics RCV000577786 SCV000886353 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004275 SCV001163151 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009371 SCV001169224 pathogenic Cystic fibrosis; CFTR-related disorders 2015-07-03 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Invitae RCV000577786 SCV001578414 pathogenic Cystic fibrosis 2020-08-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 614 of the CFTR protein (p.Asp614Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs201124247, ExAC 0.02%). This variant has been observed in combination with another CFTR variant in individuals affected with congenital absence of vas deferens and cystic fibrosis (PMID: 12454843, 16478680, 17413420, 21679131). ClinVar contains an entry for this variant (Variation ID: 53403). This variant has been reported to affect CFTR protein function (PMID: 9736778). For these reasons, this variant has been classified as Pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577786 SCV000679343 not provided Cystic fibrosis no assertion provided literature only

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