ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.489+3A>G (rs377729736)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047162 SCV000075175 pathogenic Cystic fibrosis 2018-12-24 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs377729736, ExAC 0.06%). This variant has been observed in combination with another CFTR variant in individuals affected with cystic fibrosis (PMID: 11810271). This variant has also been observed in individuals affected with sarcoidosis, azoospermia, congenital absence of the vas deference, or in an asymptomatic 8 year old with a pathogenic CFTR variant on the opposite chromosome (in trans) (PMID: 10980579, 20021716, 22020151, 19893581). This variant is also known as 621+3A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 53971). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change results in aberrant splicing of the CFTR primary transcript (PMID: 19893581, 11810271). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000507054 SCV000344240 uncertain significance not provided 2017-11-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507054 SCV000601124 likely pathogenic not provided 2017-05-14 criteria provided, single submitter clinical testing
GeneDx RCV000507054 SCV000617530 uncertain significance not provided 2017-07-28 criteria provided, single submitter clinical testing The c.489+3A>G variant in the CFTR gene, also referred to as c.621+3A>G, has been reported in the heterozygous state patients with sarcoidosis, CAVD, and azoospermia without CAVD (Bombieri et al., 2000; Amato et al., 2012; Gallati et al., 2009). This variant reduces the quality of the splice donor site in intron 4, and may cause abnormal gene splicing. The c.489+3A>G variant is observed in 30/50716 (0.06%) alleles in the ExAC dataset (Lek et al., 2016). We interpret c.489+3A>G as a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000047162 SCV000697029 likely pathogenic Cystic fibrosis 2020-01-16 criteria provided, single submitter clinical testing CFTR c.489+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: 5/5 tools via Alamut predict that the variant abolishes or weakens the canonical 5' splicing donor site. This is further supported by experimental evidence reporting an impact on mRNA splicing as corroborated by two independent studies that showed a reproducible distribution of transcripts resulting from activation of an alternate splice site (approx 28.3%) and transcripts resulting from complete skipping of exon 4 (approx 6.8%) in addition to levels of wild-type transcripts (approx remaining 65%) (Tzetis_2001, Forzan_2010). Furthermore, the pattern of abnormal splicing demonstrated by this variant is very similar to that of c.489+1G>T (legacy name 621+1G>T) considered to be a well recognized pathogenic CFTR variant (Tzetis_2001) (ACMG PP3, PS3). The variant allele was found at a frequency of 0.00025 in 247812 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR allowing no conclusion about variant significance. c.489+3A>G has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Tzetis_2001, Kanavakis_2003, Soltysova_2018) and other CFTR-related diseases such as CBAVD (e.g. Amato_2012), azoospermia (e.g. Gallati_2009), sarcoidosis (Bombieri_2000), and chronic pancreatitis (Sofia_2016). These data, when ascertained conservatively, limited to patients with a confirmed diagnosis of CF, support the notion that the variant is likely to be associated with disease (ACMG PP1, PM3). At-least one report of an asymptomatic 8 year old girl harboring this variant in trans with another pathogenic CFTR variant (p.Q552*) has been ascertained (Forzan_2010). This patient had inconsistent sweat chloride levels ranging from 49-75 mEq/L in three independent measurements and the possibility of subclinical disease cannot be entirely ruled out. In addition, the variant was also reported to have been observed in cis with 4332delTG (legacy name) in a CF patient harboring 2183AA/G (legacy name) on the other allele (Loumi_2008) (ACMG BP2). However, to our knowledge, there are no additional reports of this co-occurrence to substantiate this finding. CFTR2 database states this variant to have varying consequences. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as pathogenic (n=1), likely pathogenic (n=1), and uncertain significance (n=4). Some of the submitters provide overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic for CF mindful of the variable expressivity observed for this disorder.
Mendelics RCV000047162 SCV000886393 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000047162 SCV000916177 uncertain significance Cystic fibrosis 2018-12-07 criteria provided, single submitter clinical testing The CFTR c.489+3A>G variant, also referred to as c.621+3A>G, has been reported in six studies in which it is identified in a compound heterozygous state in at least six individuals and in a heterozygous state in at least five individuals with varying clinical consequences including cystic fibrosis, CBAVD, azoospermia, and sarcoidosis (Bombieri et al. 2000; Tzetis et al. 2001; Loumi et al. 2008; Gallati et al. 2009; Forzan et al. 2010; Amato et al. 2012). However, one study found that the frequency of affected individuals carrying the variant was lower than expected based on the allele frequency in the control population (Forzan et al. 2010). The c.489+3A>G variant occurs in the splice region and RT-PCR analysis revealed that the variant generates both correctly spliced and incorrectly spliced products, suggesting aberrant splicing with a possibility of some residual activity of the CFTR protein (Tzetis et al. 2001). The c.489+3A>G variant has been reported at a frequency of 0.000592 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the conflicting evidence and the clinical variability found in patients with this variant, the c.489+3A>G variant is classified as a variant of unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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