ClinVar Miner

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

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Total submissions: 8
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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 not specified 2018-09-19 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.
Integrated Genetics/Laboratory Corporation of America RCV000587283 SCV000696869 uncertain significance not provided 2017-03-14 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1684G>A (p.Val562Ile) variant involves the alteration of a conserved nucleotide resulting in a conservative amino acid substitution in the NBD1 domain of the CFTR protein. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 20/120834 control chromosomes at a frequency of 0.0001655, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in the literature in patients with a wide spectrum of phenotypes ranging from asymptomatic to CF, CBAVD, infertility, diffuse bronchiectasis and idiopathic chronic pancreatitis, many of whom have no information regarding other variants present. Some of the earlier reports of this variant (such as Claustres_HM_2000) suffered from a lack of comprehensive genotyping, therefore the possibility of undectected variants causative of the reported phenotype could not be ruled out. Several reported patients also carry another pathogenic variant in cis (such as the 5T allele with a longer TG repeat number) in combination with another pathogenic variant in trans that could have explained some of the symptoms reported. 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) and cited in a peer-reviewed report by Ratbi et al (Ratbi_HR_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 and cited in Roxo-Rosa_PNAS_2006. These reports provide additional supporting evidence that the variant of interest was not causative of disease in these patients. 2 Independent functional studies have shown the variant to have no impact on either of CFTR trafficking, the maturation process, or channel activity (Roxo-Rosa_2006, Fresquet_2011). The proposed best practice guidelines for CFTR testing (Dequeker_EJHG_2009) list this variant in the CFTR-related disorders associated category without additional evidence to evaluate. Due to this conflicting clinical and functional data, this variant is classified as a VUS-possibly benign variant.
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 Conflicting evidence
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.

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