chr7-117592419-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP2PP3PP5

The NM_000492.4(CFTR):​c.2252G>T​(p.Arg751Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000959 in 1,460,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R751C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

4
9
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7

Conservation

PhyloP100: 4.33

Publications

9 publications found
Variant links:
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]
CFTR Gene-Disease associations (from GenCC):
  • cystic fibrosis
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
  • congenital bilateral absence of vas deferens
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary chronic pancreatitis
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.818
PP5
Variant 7-117592419-G-T is Pathogenic according to our data. Variant chr7-117592419-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235245.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFTRNM_000492.4 linkc.2252G>T p.Arg751Leu missense_variant Exon 14 of 27 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkc.2252G>T p.Arg751Leu missense_variant Exon 14 of 27 1 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000401
AC:
1
AN:
249372
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000959
AC:
14
AN:
1460366
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
726452
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33430
American (AMR)
AF:
0.00
AC:
0
AN:
44578
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26018
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86000
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53354
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.0000126
AC:
14
AN:
1111228
Other (OTH)
AF:
0.00
AC:
0
AN:
60304
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cystic fibrosis Uncertain:4
Mar 13, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R751L variant (also known as c.2252G>T), located in coding exon 14 of the CFTR gene, results from a G to T substitution at nucleotide position 2252. The arginine at codon 751 is replaced by leucine, an amino acid with dissimilar properties. This alteration, along with the deltaF508 pathogenic mutation, was described in an individual who presented with pancreatic sufficient cystic fibrosis. However, information if this alteration was in cis or trans with deltaF508 was not available (Goubau C et al. Thorax 2009; 64:683-91). Functional studies demonstrated that this variant is functional and biochemical responses were similar to the wildtype CFTR protein level (Haq IJ et al. Am J Physiol Lung Cell Mol Physiol, 2021 Feb;320:L288-L300). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Jul 22, 2021
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 21, 2018
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 19, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 751 of the CFTR protein (p.Arg751Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 19318346, 33296276). ClinVar contains an entry for this variant (Variation ID: 235245). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CFTR protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 33296276). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:2
May 06, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: CFTR c.2252G>T (p.Arg751Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249372 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2252G>T has been reported in the literature in individuals affected with Cystic Fibrosis who were reported as compound heterozygous with pathogenic variants (e.g. Goubau_2009, Coffey_2017, Haq_2021). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Haq_2021, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 27837951, 38352056, 19318346, 33296276). ClinVar contains an entry for this variant (Variation ID: 235245). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Jun 26, 2019
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The CFTR c.2252G>T; p.Arg751Leu variant (rs397508357) is reported in the literature in an individual affected with pancreatic-sufficient cystic fibrosis that also carried the pathogenic p.Phe508del variant (Goubau 2009). In testing performed at ARUP, the p.Arg751Leu variant has also been seen in a newborn with elevated sweat chloride that also carried a nonsense variant in CFTR. This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 751 is moderately conserved and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Arg751Leu variant is uncertain at this time. References: Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009 Aug;64(8):683-91. -

not provided Pathogenic:1
Mar 30, 2015
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Sep 27, 2023
Baylor Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Uncertain:1
Jul 22, 2021
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D;.;D;.
Eigen
Benign
0.077
Eigen_PC
Benign
0.047
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.83
T;T;T;T
M_CAP
Pathogenic
0.50
D
MetaRNN
Pathogenic
0.82
D;D;D;D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Uncertain
2.4
M;.;.;.
PhyloP100
4.3
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-2.6
D;.;D;.
REVEL
Uncertain
0.55
Sift
Uncertain
0.0070
D;.;D;.
Sift4G
Uncertain
0.0020
D;.;D;.
Polyphen
0.28
B;.;.;.
Vest4
0.79
MVP
0.99
MPC
0.0050
ClinPred
0.90
D
GERP RS
5.5
Varity_R
0.56
gMVP
0.52
Mutation Taster
=34/66
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs397508357; hg19: chr7-117232473; API