ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1558G>A (p.Val520Ile) (rs77646904)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046339 SCV000074352 uncertain significance Cystic fibrosis 2019-11-07 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 520 of the CFTR protein (p.Val520Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs77646904, ExAC 0.08%). This variant has been reported in individuals affected with cystic fibrosis, however a second CFTR variant was not identified or specified in some of these individuals (PMID: 16596947, 17020473, 12167682, 19324992). It has also been reported in an individual affected with congenital bilateral absence of the vas deferens (PMID: 14998948). ClinVar contains an entry for this variant (Variation ID: 35825). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Val520Phe) has been determined to be pathogenic (PMID: 23974870, 23891399). This suggests that the valine residue may be important for CFTR protein function, though experimental studies have not been performed for the p.Val520Ile variant, therefore the functional significance of this amino acid substitution is unknown. 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589201 SCV000110846 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000855641 SCV000603040 uncertain significance not specified 2018-12-06 criteria provided, single submitter clinical testing The CFTR c.1558G>A; p.Val520Ile variant (rs77646904) has been reported in the literature in individuals with mild or atypical cystic fibrosis, including in individuals with congenital bilateral absence of the vas deferens (Bienvenue 2005, Danziger 2004, Groman 2002, Schwartz 2009). Additionally, another variant in the same codon, p.Val520Phe, is a known pathogenic variant (Sosnay 2013). The p.Val520Ile variant is reported in ClinVar (Variation ID: 35825) and is found in general population with an overall allele frequency of 0.01% (38/276844 alleles) in the Genome Aggregation Database. The valine at codon 520 is well conserved across a variety of species, but computational programs (PolyPhen2, SIFT) do not reach a consensus as to the effect of the variant on protein function. However, due to limited information, the clinical significance of the p.Val520Ile variant is uncertain at this time. References: Bienvenu T et al. Spectrum of CFTR mutations on Reunion Island: impact on neonatal screening. Hum Biol. 2005. 77(5):705-14. Danziger KL et al. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004. 19(3):540-6. Groman JD et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002. 347(6):401-7. Schwartz K et al. Identification of cystic fibrosis variants by polymerase chain reaction/oligonucleotide ligation assay. J Mol Diagn. 2009. 11(3):211-5. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013. 45(10):1160-7.
Integrated Genetics/Laboratory Corporation of America RCV000855641 SCV000696850 uncertain significance not specified 2019-02-22 criteria provided, single submitter clinical testing Variant summary: The variant, CFTR c.1558G>A (p.Val520Ile) results in a conservative amino acid change located in the AAA+ ATPase domain and ABC transporter-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 277044 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00014 vs 0.013), allowing no conclusion about variant significance. The variant was seen in a CF patient with a mild disease who had no other CFTR mutations (Nectoux_2006) and in an Indian CF patient who has an unknown mutation on his other CF chromosome (Sick Kids database). The variant was also observed in a CF patient, who, in addition to the V502I variant, also carried a 2347delG and deltaF508 mutations (Bienvenu_2005). This co-occurrence indicates that the variant might be in the benign spectrum. It has also been reported in a CBAVD patient who is reported to carry 3601-3C>A (c.3469-3C>A as per HGVS nomenclature) variant in other allele (Danziger_CFTR_HR_2004). One publication, Claustres_2017, reports the variant in trans with p.K710X being observed in an asymptomatic compound heterozygote individual. These reports however do 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. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000046339 SCV000795529 uncertain significance Cystic fibrosis 2017-11-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV001012150 SCV001172571 uncertain significance Inborn genetic diseases 2020-01-06 criteria provided, single submitter clinical testing Conflicting evidence
Illumina Clinical Services Laboratory,Illumina RCV001163392 SCV001325424 uncertain significance CFTR-related disorders 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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