ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1684G>A (p.Val562Ile) (rs1800097)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000587283 SCV000225790 uncertain significance not provided 2017-10-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999854 SCV000603058 likely benign none provided 2019-07-26 criteria provided, single submitter clinical testing
Invitae RCV000029484 SCV000625728 uncertain significance Cystic fibrosis 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 562 of the CFTR protein (p.Val562Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs1800097, ExAC 0.05%). This variant has been reported in individuals affected with CFTR-related disorders including congenital absence of the vas deferans, oligospermia, chronic pancreatitis, and cystic fibrosis (PMID: 1379210, 20021716, 21520337, 23951356, 9239681, 16189704, 25667564, 17331079, 20691141, 19810821). In many cases, this variant was observed on the same chromosome (in cis) with CFTR variants TG11-5T and/or p.Ala1006Glu (PMID: 16189704, 17331079, 20691141, 19810821, 17329263, 25910067). This variant is also known as 1816G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 35830). Experimental studies have shown that this missense change does not affect CFTR expression or function (PMID: 17098864, 21708286). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001526855 SCV000696869 likely benign not specified 2021-06-16 criteria provided, single submitter clinical testing Variant summary: CFTR c.1684G>A (p.Val562Ile) results in a conservative amino acid change located in the AAA+ ATPase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. However, a recently developed integrative tool for in-silico analysis of missense variants in the CFTR gene (CYSMA), reporting a sensitivity of 89% and a specificity of 85% classified this variant as a True Negative (Sasorith_2020). This tool generates a set of computationally derived data, ranging from evolutionary conservation to functional observations from threedimensional structures, provides all available allelic frequencies, clinical observations, and references for functional studies. The variant allele was found at a frequency of 0.00014 in 250586 control chromosomes (gnomAD and publications). 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. c.1684G>A, has been reported in the literature in individuals affected with a wide spectrum of phenotypes ranging from asymptomatic to CF, CBAVD, infertility, diffuse bronchiectasis and idiopathic chronic pancreatitis, many of whom were not uniformly analyzed and had non-informative genotypes (Braekeleer_1996, Peuchal_1999, Telleria_1999, Grangeia_2004, Cohn_2005, Claustres_2017, Lucarelli_2017). These data do not allow any conclusion about variant significance. In addition, several publications have reported this variant in cis as c.[1210-34_1210-6TG[11]T[5];1684G>A] (TG11T5, T5, A1006E) in combination with another pathogenic variant in trans that could have explained some of the symptoms reported (McGinniss_2005, Alonso_2007, Ratbi_2007, Lucarelli_2015, Sofia_2018). Of note, at-least one patient homozygous for 2347delG with this variant in cis on both his alleles has been reported in an unpublished study (Giordan et al) (cited by Ratbi_2007). Similarly, at-least 2 unaffected patients with this variant and p.F508del in trans have been reported as a personal communication with C. Barreto (cited by Roxo-Rosa_2006). Recently, this variant genotype (c.[1210-34_1210-6TG[11]T[5];1684G>A]) was reported with a hemizygous causative highly penetrant truncation variant in the X-linked ADGRG2 gene (c.251C>G, p.Ser84*) in a patient with CBAVD, bilateral epididymis enlargement, azoospermia and hypovolemia (Pagin_2020). The authors concluded that the presence of the CFTR variant in this patient may be incidental and that the loss of function variant in ADGRG2 is sufficient to produce the CAVD phenotype. These reports provide additional supporting evidence that the variant of interest was not causative of disease in these patients. Three independent functional studies report no effects on either of CFTR trafficking, the maturation process, channel activity or mRNA expression levels (Roxo-Rosa_2006, Fresquet_2011, Raraigh_2018). The CFTR2 database reports this variant as not causative of CF when combined with another CF-causing variant. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and conflicting assessments (likely benign, n=1, VUS, n=5, pathogenic, n=1). Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the non-informative genotypes, co-occurrence in cis with a pathogenic variant, alternative molecular basis of disease in settings of CFTR-related conditions such as infertility and lack of functional evidence outlined above, the variant was re-classified as likely benign.
SIB Swiss Institute of Bioinformatics RCV000029484 SCV000803609 uncertain significance Cystic fibrosis 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:17098864). BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:17329263).
Mendelics RCV000029484 SCV000886351 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV001012721 SCV001173210 pathogenic Inborn genetic diseases 2019-03-02 criteria provided, single submitter clinical testing The p.V562I variant (also known as c.1684G>A), located in coding exon 13 of the CFTR gene, results from a G to A substitution at nucleotide position 1684. The valine at codon 562 is replaced by isoleucine, an amino acid with highly similar properties. The (TG)11-5T variant is located in intron 9 of the CFTR gene within the poly-thymidine tract, and results in decreased efficiency of exon 10 splicing. The 5T variant in trans with a pathogenic CFTR mutation, or in the homozygous state, has been associated with CFTR-related disorders, including bronchiectasis (Sosnay et al. Pediatr Clin North Am 2016;63(4):585-98), acute recurrent or chronic pancreatitis (Werlin et al. J Pediatr Gastroenterol Nutr 2015; 60(5):675-9, Masson et al. PLoS One 2013; 8(8):e73522), and congenital bilateral absence of the vas deferens (CBAVD) (Bombieri et al. J Cyst Fibros 2011;10 Suppl 2:S86-102). The p.V562I and (TG)11-5T variants are often seen in cis and have been reported as part of a complex allele, [p.V562I;(TG)11-5T], which has been identified in trans with a known pathogenic mutation in individuals with CBAVD and in an individual with positive newborn screening (Ratbi I et al. Hum. Reprod., 2007 May;22:1285-91; Prach L et al. J Mol Diagn, 2013 Sep;15:710-22). A similar complex allele including a third variant, [p.V562I;(TG)11-5T;p.A1006E] has been reported as more likely to result in classic cystic fibrosis with pancreatic sufficiency when in trans with a known pathogenic mutation (Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75). Based on the available evidence, the [p.V562I;(TG)11-5T] complex allele is classified as disease modifying.
Illumina Clinical Services Laboratory,Illumina RCV001163395 SCV001325427 uncertain significance CFTR-related disorders 2017-04-27 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000587283 SCV001714833 uncertain significance not provided 2020-04-22 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000029484 SCV001822076 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing

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