ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1684G>C (p.Val562Leu) (rs1800097)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046421 SCV000074434 uncertain significance Cystic fibrosis 2019-10-09 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 562 of the CFTR protein (p.Val562Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs1800097, ExAC 0.009%). This variant has been reported in individuals affected with cystic fibrosis (PMID: 8956039, 24586523, 28544683). This variant is also known as c.1816G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 53341). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000417570 SCV000521023 likely pathogenic not provided 2015-12-18 criteria provided, single submitter clinical testing The V562L variant in the CFTR gene has been reported previously in trans with the I507del pathogenic variant in a patient with mild-moderate CF disease and pancreatic sufficiency (Hughes et al., 1996). The V562L variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V562L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position within the ABC transporter 1 domain that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same residue (V562I) has been reported in association with CAVD and milder CFTR-related disorders (Ratbi et al., 2007). The V562L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Integrated Genetics/Laboratory Corporation of America RCV000417570 SCV000696870 uncertain significance not provided 2016-10-19 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1684G>C (p.Val562Leu) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. However, these predictions have not been confirmed via any in vitro/vivo functional studies by the time of classification. This variant was found in 5/120970 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant has been reported in affected individuals including a mild CF case with delta I507 in trans (Hughes_1996), a bronchiectasis case with 5T-11TG in trans (Casals_2004), a CF case with no variant detected in trans (Zietkiewicz_2013) and a patient with renal phenotype and positive sweat test with 5T in cis (Pavone_2010). This variant has also been detected in random European individuals (Bombieri_2000). Taken together, this variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000417570 SCV000883570 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing The CFTR c.1684G>C, p.Val562Leu variant (rs1800097) has been reported in an individual with mild cystic fibrosis and pancreatic sufficiency, and found in-trans with p.Ile507del (Hughes 1996). It is listed in ClinVar (Variation ID: 53341), and observed in the Genome Aggregation Database general population database at a frequency of 0.005 percent (14/276196 alleles). The valine at residue 562 is highly conserved, but computational algorithms (Align GVGD: C25; Mutation Taster: disease causing; PolyPhen-2: benign; SIFT: damaging) are inconclusive on the variant's impact on the protein. Due to the limited information regarding this variant, its clinical significance could not be determined with certainty. References: Hughes D et al. Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes. Hum Mutat. 1996; 8(4):340-7.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825895 SCV000967380 uncertain significance not specified 2018-12-27 criteria provided, single submitter clinical testing Notes: reported as compound het with 5T in one individual with bronchiectisis; a single het in an individual with CF; and possibly as a double het in an individ ual with CF. Computation predictions are mixed.

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