7-117594991-G-T

Variant names:

• chr7-117594991-G-T
• rs397508395
• NM_000492.4:c.2552G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.2552G>T​(p.Arg851Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,594 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. R851Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 9.06
• Publications: 10 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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, 0.961
• PP5: Variant 7-117594991-G-T is Pathogenic according to our data. Variant chr7-117594991-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53511.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2552G>T	p.Arg851Leu	missense_variant	Exon 15 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2552G>T	p.Arg851Leu	missense_variant	Exon 15 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151976 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460618 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726716

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111180

Other (OTH) AF: 0.00 AC: 0 AN: 60330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151976 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Uncertain:1 Other:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

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 851 of the CFTR protein (p.Arg851Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CFTR-related disease (PMID: 9598638, 20167849, 27086061). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53511). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Jan 17, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R851L pathogenic mutation (also known as c.2552G>T), located in coding exon 15 of the CFTR gene, results from a G to T substitution at nucleotide position 2552. The arginine at codon 851 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in the homozygous state and/or in conjunction with other CFTR variant(s) in individual(s) with features consistent with cystic fibrosis or CFTR-related disorders; in at least one instance, the variants were identified in trans (Bernardino AL et al. Genet Test, 2000;4:69-74; Bienvenu T et al. Am J Respir Crit Care Med, 2010 May;181:1078-84; Trujillano D et al. J Med Genet, 2013 Jul;50:455-62; Gaitch N et al. Pancreatology, 2016 Apr;16:515-22). In an assay testing CFTR function, this variant showed a functionally abnormal result (Bihler H et al. J Cyst Fibros, 2024 Jul;23:664-675). This nucleotide position is well conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Nov 05, 2018

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 12, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.2552G>T (p.Arg851Leu) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251312 control chromosomes. The variant, c.2552G>T, has been reported in the literature in compound heterozygosity with p.F508del in an individual with idiopathic chronic pancreatitis and bronchitis (Bernardino_2003), and in an individual with congenital bilateral absence of the vas deferens (CBAVD) and a sweat chloride of 74 mmol/L (de la Taille_1998); in a third individual who had diffuse bronchiectasis, but was reported with normal sweat chloride value, the variant was found in compound heterozygosity with p.Arg553* (Bienvenu_2010). The variant was also reported in homozygous state in an individual diagnosed with CFTR-RD (Trujillano_2013). In addition, the variant allele was found in individuals diagnosed cystic fibrosis (CF) or CF-related phenotypes (e.g. Claustres_2000, Perez_2007, da Silva Filho_2020), however in these patients the second allele was not specified. Lastly, a case of "presumed" homozygosity in two children from a consanguineous family who reportedly died due to CF (therefore, not genotyped) has been reported (Casals_1997). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in <10% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 14526128, 20167849, 9439669, 10923036, 27086061, 16963320, 23687349, 32819855, 9598638, 38388235). ClinVar contains an entry for this variant (Variation ID: 53511). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 01, 2021

Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

This variant was first described in a carrier father who had two deceased children who died from Cystic Fibrosis (CF), and these kids were probably homozygous to this variant (due to parent consanguinity). However, that has never been confirmed (Casals et al. 1997). This imprecision led to the belief that this variant is pathogenic. Despite this variant has been classified and reclassified over the course of time as pathogenic and lately as likely pathogenic (by Mendelics and Invitae), new functional evidence has shown that this variant does not alter CFTR function even when located in the same allele (in cis) as NM_000492.4(CFTR):1052C>G; p.Thr351Ser) and in trans with the most common pathogenic variant p.Phe508del (NM_000492.4(CFTR):1521_1523delCTT). Although in a pathogenic range due to its very low frequency in public databases (absent in ExAc but seen twice in GnomAd (in a non-Finnish European and in a person of unknown ethnicity), the aminoacid change promoted by this missense variant is located in the transition between the cytoplasm and the transmembrane portions of CFTR, at the beginning of the second transmembrane domain, which does not implicate in an abrupt abnormality in the CFTR protein. Also, there is another missense variant in the same nucleotide position which has been classified as having uncertain significance (NM_000492.4(CFTR):c.2552G>A; p.Arg851Gln). Besides, prediction tools are very disagreeable when predicting the deleteriousness of this variant. Therefore, the controversial data existing to date regarding this variant leads to the classification of uncertain significance. Brief Medical History: the patient was diagnosed with NBS and treated with pancreatic enzymes until the age of 2-3 y.o. The mother decided to stop giving any medication. Since then, the patient presented normal thrive and growth, normal stature, and was eutrophic throughout her life, which would not be expected given the patient's genotype. The patient is now 22 y.o. and has no history of chronic lung infections nor exacerbations or any other features compatible with Cystic Fibrosis. Sweat chloride tests have always been within borderline range (30-59 mM). Also, the patient is pancreatic-sufficient. In January 2020, the patient provided stool samples. Fecal elastase-1 levels in feces samples are within the normal range of the assay, which is a biomarker of pancreatic exocrine sufficiency. Other biochemical and hematological measurements to verify liver function were also normal throughout the patient's life. -

CFTR-related disorder Pathogenic:1

Dec 07, 2017

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PhyloP100		9.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;.;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0070	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.89
MutPred		0.85		Loss of sheet (P = 0.0063);.;.;.;
MVP		1.0
MPC		0.0048
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.80
Mutation Taster		=7/93	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

Other links and lift over

dbSNP: rs397508395; hg19: chr7-117235045;