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rs1800098

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_000492.4(CFTR):c.1727G>C(p.Gly576Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00499 in 151922 control chromosomes in the gnomAD Genomes database, including 3 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

Genomes: 𝑓 0.0050 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0051 ( 8 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

3
8
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:14B:7

Conservation

PhyloP100: 5.67

Links

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000492.4
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0150203705).
BS2
?
High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFTRNM_000492.4 linkuse as main transcriptc.1727G>C p.Gly576Ala missense_variant 13/27 ENST00000003084.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.1727G>C p.Gly576Ala missense_variant 13/271 NM_000492.4 P2P13569-1

Frequencies

GnomAD3 genomes
AF:
0.00499
AC:
758
AN:
151922
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00184
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00728
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00586
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.00729
Gnomad OTH
AF:
0.00622
GnomAD3 exomes
AF:
0.00507
AC:
1270
AN:
250304
Hom.:
8
AF XY:
0.00515
AC XY:
697
AN XY:
135446
show subpopulations
Gnomad AFR exome
AF:
0.00193
Gnomad AMR exome
AF:
0.00542
Gnomad ASJ exome
AF:
0.000498
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00538
Gnomad NFE exome
AF:
0.00793
Gnomad OTH exome
AF:
0.00557
GnomAD4 exome
AF:
0.00699
AC:
10147
AN:
1450774
Hom.:
49
AF XY:
0.00660
AC XY:
4763
AN XY:
721602
show subpopulations
Gnomad4 AFR exome
AF:
0.00150
Gnomad4 AMR exome
AF:
0.00521
Gnomad4 ASJ exome
AF:
0.000234
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000697
Gnomad4 FIN exome
AF:
0.00550
Gnomad4 NFE exome
AF:
0.00834
Gnomad4 OTH exome
AF:
0.00586
Alfa
AF:
0.00629
Hom.:
2
Bravo
AF:
0.00486
TwinsUK
AF:
0.0108
AC:
40
ALSPAC
AF:
0.00934
AC:
36
ESP6500AA
AF:
0.00250
AC:
11
ESP6500EA
AF:
0.00664
AC:
57
ExAC
AF:
0.00513
AC:
623
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00693
EpiControl
AF:
0.00718

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:14Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cystic fibrosis Uncertain:3Benign:5
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 16, 2020- -
Likely benign, criteria provided, single submitterclinical testingCounsylNov 19, 2017- -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jul 01, 2017- -
Benign, criteria provided, single submitterclinical testingMendelicsAug 22, 2023- -
Benign, criteria provided, single submitterclinical testingInvitaeNov 04, 2022- -
Benign, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityApr 24, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 28, 2023The 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, the in silico prediction for this alteration is inconclusive. 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. -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabMay 18, 2021- -
not provided Pathogenic:1Uncertain:6
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 12, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 17, 2017The 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. -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 27, 2020The 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. -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, Revvity OmicsJul 06, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJun 21, 2023The CFTR c.1727G>C (p.Gly576Ala) variant has been reported in the published literature in individuals with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 9272157 (1997), 10875853 (2000), 10653141 (2000), 17329263 (2007), 21520337 (2011), 28603918 (2017)), pancreatitis (PMID: 23951356 (2013), 33260873 (2020), 20460946 (2010), 19812525 (2010), 15987793 (2005), 17489851 (2007)), bronchiectasis (PMID: 8644755 (1995), 7543317 (1995), 15151509 (2004), 16189704 (2005), 25797027 (2015)) as well as in healthy individuals (PMID: 12127423 (2002), 23974870 (2013), 29589582 (2018)) . In addition, splicing studies in the published literature demonstrate that the variant causes reduced levels of normal CFTR mRNA that is further decreased when the variant is on the same chromosome as the p.Arg668Cys variant (PMID: 12719375 (2003)). Functional studies report mildly altered CFTR chloride conductance in individuals with both variants (PMID: 22678879 (2012)). 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. Based on the available information, we are unable to determine the clinical significance of this variant. -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2023CFTR: PM3:Very Strong, PM2, PS3:Moderate -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJan 07, 2015- -
CFTR-related disorders Pathogenic:1Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Uncertain significance, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 16, 2020- -
Pathogenic, criteria provided, single submittercurationCFTR-FranceMar 26, 2018- -
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 1992- -
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 16, 2023Variant 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. -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 31, 2015Variant 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
Uncertain significance, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalMay 14, 2015c.1727G>C and c.2002C>T found in cis -
Lung disease, non-specific Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalMay 14, 2015c.1727G>C and c.2002C>T found in cis -
CFTR-related condition Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, Part of Exact SciencesOct 11, 2023The 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.052
T
BayesDel_noAF
Pathogenic
0.16
Cadd
Pathogenic
26
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T;.;T;.
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.015
T;T;T;T
MetaSVM
Uncertain
0.25
D
MutationAssessor
Benign
0.070
N;.;.;.
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
0.11
N;.;N;.
REVEL
Pathogenic
0.67
Sift
Benign
0.26
T;.;T;.
Sift4G
Benign
0.14
T;.;T;.
Polyphen
0.91
P;.;.;.
Vest4
0.87
MVP
0.99
MPC
0.0040
ClinPred
0.066
T
GERP RS
4.8
Varity_R
0.49
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.42
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.42
Position offset: 39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1800098; hg19: chr7-117230454; API