rs1800098

chr7-117590400-G-Cchr7-117590400-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

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:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (49 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:14 B:7
• Conservation: PhyloP100: 5.67

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_benign. Variant got -2 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
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1727G>C	p.Gly576Ala	missense_variant	13/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1727G>C	p.Gly576Ala	missense_variant	13/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 758 AN: 151922 Hom.: 3 Cov.: 32

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

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 Cov.: 30 AF XY: 0.00660 AC XY: 4763 AN XY: 721602

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

GnomAD4 genome AF: 0.00499 AC: 758 AN: 152038 Hom.: 3 Cov.: 32 AF XY: 0.00480 AC XY: 357 AN XY: 74330

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00727

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00586

Gnomad4 NFE AF: 0.00729

Gnomad4 OTH AF: 0.00616

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:4 Uncertain:14 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:3 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Nov 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 24, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 05, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Sep 16, 2020	- -

not provided Pathogenic:1 Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CFTR: PM3:Very Strong, PM2, PS3:Moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 21, 2023	The 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 27, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 07, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2017	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. -

CFTR-related disorder Pathogenic:1 Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 11, 2023	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. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Mar 26, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Sep 16, 2020	- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1992	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 31, 2015	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2023	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. -

Chronic sinusitis Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

May 14, 2015

c.1727G>C and c.2002C>T found in cis -

Lung disease, non-specific Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

May 14, 2015

c.1727G>C and c.2002C>T found in cis -

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	Uncertain	25
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

Other links and lift over

dbSNP: rs1800098; hg19: chr7-117230454;