ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1727G>C (p.Gly576Ala) (rs1800098)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000029486 SCV000074458 benign Cystic fibrosis 2019-12-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078981 SCV000110849 uncertain significance not provided 2018-04-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155472 SCV000205164 uncertain significance not specified 2015-07-31 criteria provided, single submitter clinical testing 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000078981 SCV000281428 uncertain significance not provided 2015-01-07 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
GeneDx RCV000078981 SCV000329248 uncertain significance not provided 2017-03-17 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000155472 SCV000601059 uncertain significance not specified 2017-04-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000155472 SCV000603022 uncertain significance not specified 2018-07-03 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America RCV000155472 SCV000696871 likely benign not specified 2017-07-13 criteria provided, single submitter clinical testing Variant summary: CFTR c.1727G>C (p.Gly576Ala) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains 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 0.005 in 280650 control chromosomes in the gnomAD database, including 7 homozygotes. This frequency is not higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.005 vs 0.013), allowing no conclusion about variant significance, though the 7 homozygotes are suggestive of a benign role for the variant. The c.1727G>C variant has been reported in the literature in several individuals affected with Non-classic Cystic Fibrosis and numerous individuals with CBAVD; however, the variant is frequently in complex with other variants, typically D443Y and R668C, making interpretation of the variant effect difficult. Functional studies that assessed the effect of the variant in isolation suggest that the variant: 1) does not alter CFTR protein expression, but may slightly reduce CFTR conductance (El-Seedy_2012); 2) does not inhibit CFTR maturation or channel function (Sosnay_2013); and 3) may cause exon 13 skipping, the physiological consequences of which are unknown (Bergougnoux_2015). Overall, the most pronounced variant effect results in >50%-90% of normal activity, suggesting a mild effect of the variant on CFTR function. In addition, the variant has also been reported in 12 fathers unaffected by cystic fibrosis or CBAVD on the opposite chromosome of pathogenic CFTR variants, indicating a neutral impact (Sosnay_2013). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. These laboratories classify the variant with conflicting assessments: 1 benign, 6 uncertain significance, and 1 pathogenic. Based on the evidence outlined above, the variant was classified as likely benign..
Counsyl RCV000029486 SCV000800794 likely benign Cystic fibrosis 2017-11-19 criteria provided, single submitter clinical testing
Mendelics RCV000029486 SCV000886141 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078981 SCV001155238 likely benign not provided 2019-01-01 criteria provided, single submitter clinical testing
CFTR-France RCV001009484 SCV001169579 pathogenic CFTR-related disorders 2018-03-26 criteria provided, single submitter curation
Ambry Genetics RCV001012908 SCV001173426 uncertain significance Inborn genetic diseases 2020-02-07 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV001009484 SCV001325428 likely benign 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). 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.
OMIM RCV000007585 SCV000027786 pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 1992-04-01 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582695 SCV000692322 uncertain significance Chronic sinusitis 2015-05-14 no assertion criteria provided clinical testing c.1727G>C and c.2002C>T found in cis
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000584175 SCV000692323 uncertain significance Lung disease, non-specific 2015-05-14 no assertion criteria provided clinical testing c.1727G>C and c.2002C>T found in cis

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