rs1800098
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_000492.4(CFTR):c.1727G>C(p.Gly576Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0068 in 1,602,812 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.1727G>C | p.Gly576Ala | missense_variant | Exon 13 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.00499 AC: 758AN: 151922Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00507 AC: 1270AN: 250304Hom.: 8 AF XY: 0.00515 AC XY: 697AN XY: 135446
GnomAD4 exome AF: 0.00699 AC: 10147AN: 1450774Hom.: 49 Cov.: 30 AF XY: 0.00660 AC XY: 4763AN XY: 721602
GnomAD4 genome 0.00499 AC: 758AN: 152038Hom.: 3 Cov.: 32 AF XY: 0.00480 AC XY: 357AN XY: 74330
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:7
- -
- -
CFTR: PM3:Very Strong, PM2, PS3:Moderate -
The CFTR c.1727G>C (p.Gly576Ala) variant has been reported in the published literature in individuals affected with clinical manifestations associated with cystic fibrosis (PMIDs: 17489851 (2007), 24586523 (2014), 36409994 (2022)), pancreatitis (PMIDs: 15987793 (2005), 17489851 (2007), 20460946 (2010)), congenital bilateral absence of the vas deferens (CBAVD) (PMID: 8801929 (2017)), and other CFTR-related disorders (PMIDs: 32784480 (2020), 33020115 (2020)). However, it was also identified in reportedly healthy individuals or with mild symptoms (PMIDs: 10922395 (2000), 22678879 (2012), see also CFTR-France, https://cftr.chu-montpellier.fr/ and CFTR2, http://cftr2.org/). Functional studies indicated that this variant causes exon skipping (PMID: 12719375 (2003), 19910374 (2010), 25797027 (2015), 33341408 (2021)). Other studies reported this variant had normal (PMID: 23974870 (2013), 25824995 (2015)) or reduced activity and/or protein (PMID: 22678879 (2012), 35418593 (2022), 36552859 (2022), 38388235 (2024)). The variant is responsive to pharmacological modulators, however, the response in patients may not be as expected (PMID: 35527187 (2022), 37147251 (2023)). The frequency of this variant in the general population, 0.0092 (241/26108 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Therefore, this variant is unlikely to be associated with classic CF. It could be a neutral variant or a variant that is associated with CFTR-related disorders (CFTR-RD) when it occurs with a CF-causing pathogenic variant on the opposite chromosome. -
BS1 -
The CFTR c.1727G>C; p.Gly576Ala variant (rs1800098) is reported in the medical literature in individuals with congenital bilateral absence of the vas deferens (Anguiano 1992, Gallati 2009) and in at least some unaffected individuals (El-Seedy 2012). However, the p.Gly576Ala variant is often observed on the same chromosome as p.Arg668Cys (El-Seedy 2012, Masson 2013), and the p.Arg668Cys variant is described as the pathogenic variant (Sosnay 2013). Publications shows this variant causes altered splicing (Bergougnoux 2015, Pagani 2003), but the effect on the variant protein was minimal (Bergougnoux 2015). An additional publication shows the variant protein localizes in the cell properly (El-Seedy 2012). The variant is described in the ClinVar database (Variation ID: 7165), and is found in the general population with an overall allele frequency of 0.5% (1375/276228 alleles, including 7 homozygotes) in the Genome Aggregation Database. The glycine at codon 576 is a moderately conserved nucleotide, and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Due to limited information about this variant when not in complex, the clinical significance of this variant is uncertain at this time. References: Anguiano A et al. Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis. JAMA. 1992 Apr 1;267(13):1794-7. Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015 Sep;14(5):646-53. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012 Nov;33(11):1557-65. 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. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 Aug 8;8(8):e73522. Pagani F et al. New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12. Hum Mol Genet. 2003 May 15;12(10):1111-20. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. -
The G576A variant in the CFTR gene has been reported previously, often as a complex allele in cis with R668C, in multiple individuals with non-classical cystic fibrosis, including late-onset pulmonary disease, congenital bilateral absence of the vas deferens (CBAVD), or idiopathic pancreatitis (Chillón et al., 1995; Gallati et al., 2009; Steiner et al., 2011; El-Seedy et al., 2012). In vitro functional studies of G576A demonstrated a slight reduction in CFTR chloride conductance, with a more significant decrease when G576A was part of a complex allele (El-Seedy et al., 2012). The G576A variant is a conservative amino acid substitution, which occurs at a position that is conserved across mammalian species. The G576A variant is observed in 506/66,396 (0.7%) alleles from individuals of European (non-Finnish) background including one homozygous individual in the ExAC dataset (Lek et al., 2016). In addition, the G576A variant has been associated with intermediate sweat chloride values and incomplete penetrance (Masica et al., 2015; Sosnay et al., 2013). We interpret G576A as a variant of uncertain significance. -
- -
Cystic fibrosis Uncertain:3Benign:5
- -
- -
- -
The p.G576A variant (also known as c.1727G>C), located in coding exon 13 of the CFTR gene, results from a G to C substitution at nucleotide position 1727. The glycine at codon 576 is replaced by alanine, an amino acid with similar properties. The p.G576A variant has been reported in isolation or as a part of a complex allele (in cis) with the following CFTR variants: p.G149R, p.D443Y, and p.R668C (El-Seedy A et al. Hum. Mutat., 2012 Nov;33:1557-65). The phenotypic spectrum associated with p.G576A and these complex alleles is variable and ranges from healthy individuals (p.[G576A;R668C]) to congenital bilateral absence of the vas deferens (CBAVD) (p.[D443Y;G576A;R668C] or p.G576A in isolation), to pancreatic insuficiency (p.[G576A;R668C]) and classic cystic fibrosis (CF) (p.[G149R;G576A;R668C]) (Anguiano A et al. JAMA, 1992 Apr;267:1794-7; El-Seedy A et al. Hum. Mutat., 2012 Nov;33:1557-65; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Salinas DB et al. J. Cyst. Fibros., 2015 Nov;14:714-9; Grangeia A et al. Pulmonology Mar;24:3-9). In functional studies, p.G576A was shown to increase skipping of exon 13 in human epithelial cells and multiple cell lines (Pagani F et al. Hum. Mol. Genet., 2003 May;12:1111-20; Bergougnoux A et al. J. Cyst. Fibros., 2015 Sep;14:646-53). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic CF; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance. -
- -
- -
- -
- -
CFTR-related disorder Uncertain:2Benign:2
The CFTR c.1727G>C variant is predicted to result in the amino acid substitution p.Gly576Ala. Both the c.1727G>C (p.Gly576Ala) and c.2002C>T (p.Arg668Cys) variants individually are found with global minor allele frequencies of >0.5%, including several homozygotes (gnomad.broadinstitute.org). Additionally, these two variants individually have been classified as non-CFTR disease-causing in a separate study (see supplemental table 2 in Sosnay et al. 2013. PubMed ID: 23974870). When these variants are present on the same allele, designated as c.[1727G>C, 2002C>T], this complex allele has been reported in patients with pancreatitis and other CFTR-related disorders, including pulmonary disease and congenital bilateral absence of the vas deferens (see for example Gallati et al. 2009. PubMed ID: 20021716; Masson et al. 2013. PubMed ID: 23951356; El-Seedy et al. 2012. PubMed ID: 22678879). Functional studies of the c.[1727G>C; 2002C>T] variant in HeLa cells showed no impairment of CFTR glycosylation or membrane localization, but decreased chloride channel activity (El-Seedy et al. 2012. PubMed ID: 22678879). Due to conflicting findings, the clinical significance of the c.1727G>C and c.2002C>T variants is currently uncertain. -
- -
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
- -
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1Uncertain:1
- -
- -
not specified Uncertain:1Benign:1
Variant summary: CFTR c.1727G>C (p.Gly576Ala) results in a non-conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0051 in 254726 control chromosomes in the gnomAD database, including 8 homozygotes. This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis phenoype (0.013), allowing no clear conclusions about variant significance, though the 8 homozygotes are suggestive of a benign role for the variant. The variant, c.1727G>C, has been widely reported in the literature in several individuals affected with features of Non-classic Cystic Fibrosis and in numerous individuals with CBAVD; however, the variant is observed frequently as a complex allele in cis with other variants, typically p.D443Y and p.R668C. This precludes the interpretation of the variant in isolation. Functional studies that assessed the effect of the variant in isolation suggest that: 1) it does not alter CFTR protein expression, but may slightly reduce CFTR conductance (El-Seedy_2012); 2) it does not inhibit CFTR maturation or channel function (Sosnay_2013); and 3) it may increase basal exon 13 skipping, the physiological consequences of which are unknown (Bergougnoux_2015, Martin_2021). Overall, the most pronounced variant effect results in >50%-90% of normal activity, suggesting a mild effect of the variant on CFTR conductance. However, the in-vivo impact of this finding is not clearly established. In addition, the variant has also been reported on the opposite chromosome of pathogenic CFTR variants in 12 fathers unaffected by cystic fibrosis or CBAVD, indicating a neutral impact (Sosnay_2013). Consistent with this report, the variant has been reported as a complex allele in healthy asymptomatic carriers with another CFTR pathogenic variant (example, Terlizzi_2019). In summary, a comprehensive and broad assessment of the published literature spanning 28 years of evolution (1993-2021) has failed to identify conclusive evidence supporting an actionable outcome for this variant when observed in isolation. Multiple submitters, including clinical diagnostic laboratories, have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments ranging from benign (n=3), likely benign (n=2) and VUS (n=13) citing overlapping evidences utilized in the context of this evaluation. One database, CFTR-France and another submitter reported a pathogenic outcome. Based on the evidence outlined above, the variant in isolation has retained its classification as likely benign. -
Variant classified as Uncertain Significance - Favor Benign. The p.Gly576Ala var iant in CFTR has been reported in >50 compound heterozygous individuals with var ying clinical diagnoses, including congenital bilateral absence of the van defer ens (CBAVD), diffuse bronchiectasis, idiopathic pancreatitis, and cystic fibrosi s (Anguiano 1992, Pignatti 1995, Dork 1997, Pelletier 2010, Sosnay 2013, El-Seed y 2012); however most of these individuals carried one or more CFTR variants in cis with this variant. This variant has been identified in 0.76% (506/66396) Eur opeans by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs1800098). The carrier frequency of this variant in individuals with CF has reported to be lower than the carrier frequency in the general population ( Sosnay 2013). Computational prediction tools and evolutionary conservation analy sis do not provide strong support for or against an impact to the protein. Howev er, in vivo studies suggest that the Gly576Ala variant may alter splicing of exo n 13 (historically exon 12; Pagani 2003). In summary, while the clinical signifi cance of the p.Gly576Ala variant is uncertain, these data suggest that it is mor e likely to be benign. -
Chronic sinusitis Uncertain:1
c.1727G>C and c.2002C>T found in cis -
Lung disease, non-specific Uncertain:1
c.1727G>C and c.2002C>T found in cis -
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at