ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.489+3A>G (rs377729736)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047162 SCV000075175 pathogenic Cystic fibrosis 2020-10-20 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. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product 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). Studies have shown that this variant is associated with skipping of exon 4 but is expected to preserve the integrity of the reading frame (PMID: 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 2020-12-28 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047162 SCV000697029 likely pathogenic Cystic fibrosis 2021-04-12 criteria provided, single submitter clinical testing Variant summary: 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. 4/4 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 (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.00025 vs 0.013), 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, Claustres_2017) 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. Ten other ClinVar submitters cite the variant as pathogenic/likely pathogenic (n=4) or uncertain significance (n=6). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001769 SCV001159395 uncertain significance not specified 2019-04-06 criteria provided, single submitter clinical testing The CFTR c.489+3A>G variant (rs377729736), also known as 621+3A>G, is reported in the literature in individuals affected with cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), and sarcoidosis, including individuals with a severe pathogenic variant on the opposite chromosome (Amato 2012, Gallati 2009, Giuliani 2010, Sermet-Gaudelus 2010, Soltysova 2018, Tzetis 2001). However, this variant has also been reported in an asymptomatic individual who carries a pathogenic nonsense variant in trans (Forzan 2010), and in cis with a truncating variant in an individual with cystic fibrosis (Loumi 2008). This variant is reported in ClinVar (Variation ID: 53971), and is found in the general population with an overall allele frequency of 0.023% (63/276,630 alleles) in the Genome Aggregation Database. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Functional studies show aberrant mRNA splicing making up about 35% of transcripts, but it is unknown if this level altered transcripts is sufficient to cause disease (Forzan 2010, Tzetis 2001). Due to conflicting information, the clinical significance of the c.489+3A>G variant is uncertain at this time. References: Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012 Jan;14(1):81-9. Forzan M et al. Is CFTR 621+3 A>G a cystic fibrosis causing mutation? J Hum Genet. 2010 Jan;55(1):23-6. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. Giuliani R et al. Identification of the second CFTR mutation in patients with congenital bilateral absence of vas deferens undergoing ART protocols. Asian J Androl. 2010 Nov;12(6):819-26. Loumi O et al. CFTR mutations in the Algerian population. J Cyst Fibros. 2008 Jan;7(1):54-9. Epub 2007 Jun 14. Sermet-Gaudelus I et al. Measurement of nasal potential difference in young children with an equivocal sweat test following newborn screening for cystic fibrosis. Thorax. 2010 Jun;65(6):539-44. Soltysova A et al. Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics. Clin Respir J. 2018 Mar;12(3):1197-1206. Tzetis M et al. Qualitative and quantitative analysis of mRNA associated with four putative splicing mutations (621+3A-->G, 2751+2T-->A, 296+1G-->C, 1717-9T-->C-D565G) and one nonsense mutation (E822X) in the CFTR gene. Hum Genet. 2001 Dec;109(6):592-601.
Baylor Genetics RCV001004432 SCV001163477 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009491 SCV001169586 pathogenic CFTR-related disorders 2018-03-09 criteria provided, single submitter curation
Ambry Genetics RCV001023206 SCV001185048 uncertain significance Inborn genetic diseases 2020-08-18 criteria provided, single submitter clinical testing The c.489+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 4 in the CFTR gene. This variant (reported as 621+3G>A) was described in four Greek individuals with severe cystic fibrosis (CF), each with a second pathogenic mutation; however, the phase (cis/trans) of the these alterations is uncertain and deletion/duplication testing was not performed. Functional testing of the alteration showed a decrease in the number of normal CFTR transcripts (Tzetis M et al. Hum Genet. 2001;109(6):592-601). In contrast, other functional and clinical evidence suggest that this variant should not be considered a CF disease-causing mutation and further studies are needed to determine if this variant is associated with CBAVD or atypical CF (Forzan M et al. J Hum Genet. 2010;55(1):23-26). The c.489+3A>G alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at Accessed January 21, 2019). Using two different splice site prediction tools, this alteration is predicted by BDGP to weaken the efficiency of the native splice donor site, but is not predicted to have a deleterious effect on this splice donor site by ESEfinder; however, direct evidence is unavailable. Since supporting evidence for this variant is conflicting at this time, the clinical significance of this variant remains unclear.
Johns Hopkins Genomics, Johns Hopkins University RCV000047162 SCV001371813 likely pathogenic Cystic fibrosis 2020-01-29 criteria provided, single submitter clinical testing CFTR variant associated with variable clinical consequences. See for phenotype information.
Nilou-Genome Lab RCV000047162 SCV001822004 likely pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing

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