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

dbSNP: rs1800097

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000587283	SCV000225790	uncertain significance	not provided	2017-10-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587283	SCV000603058	likely benign	not provided	2022-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000029484	SCV000625728	uncertain significance	Cystic fibrosis	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 562 of the CFTR protein (p.Val562Ile). This variant is present in population databases (rs1800097, gnomAD 0.03%). This missense change has been observed in individual(s) with CFTR-related disorders including congenital absence of the vas deferens, oligospermia, chronic pancreatitis, and cystic fibrosis (PMID: 1379210, 9239681, 16189704, 17329263, 17331079, 19810821, 20021716, 20691141, 21520337, 23951356, 25667564, 25910067). This variant is also known as 1816G>A. ClinVar contains an entry for this variant (Variation ID: 35830). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change does not substantially affect CFTR function (PMID: 17098864, 21708286). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV000029484	SCV001173210	likely benign	Cystic fibrosis	2022-06-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, 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	2022-01-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000029484	SCV001822076	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256003	SCV002529683	uncertain significance	Hereditary pancreatitis	2021-05-07	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003415742	SCV004106449	uncertain significance	CFTR-related condition	2023-11-30	criteria provided, single submitter	clinical testing	The CFTR c.1684G>A variant is predicted to result in the amino acid substitution p.Val562Ile. This variant was reported in a Moroccan patient with cystic fibrosis (Telleria et al. 1999. PubMed ID: 10447267). However, there was no further evidence that the p.Val562Ile variant was actually causative in this case. A later study reported cellular and genetic evidence that the p.Val562Ile variant may be benign (Roxo-Rosa et al. 2006. PubMed ID: 17098864). This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD. In ClinVar, this variant has conflicting interpretations ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/35830/). While we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Johns Hopkins Genomics, Johns Hopkins University	RCV000029484	SCV004239028	likely benign	Cystic fibrosis	2023-12-20	criteria provided, single submitter	clinical testing