7-117504291-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000492.4(CFTR):c.92G>T(p.Arg31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,612,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:12O:1

Conservation

PhyloP100: 1.90

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 76) in uniprot entity CFTR_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2548123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.92G>T	p.Arg31Leu	missense_variant	Exon 2 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.92G>T	p.Arg31Leu	missense_variant	Exon 2 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250924

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000883

AC:

129

AN:

1460396

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

726678

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000668

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:5Other:1

Mar 03, 2017

CFTR2

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: research

- -

Mar 01, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported in patients with a phenotypic consistent with cystic fibrosis and is currently classified as a variant of uncertain significance by three submitters in ClinVar. Functional studies have shown that this variant may lead to reduced protein function, however the impact of this variant is not completely understood at this time. Additionally, this CFTR variant (rs149353983) is rare (<0.1%) in large population datasets (gnomAD: 11/282294 total alleles; 0.0039%; no homozygotes). Two bioinformatic tools queried predict that this substitution would be tolerated, and the arginine residue at this position is evolutionarily conserved across most species assessed. The clinical significance of c.92G>T is uncertain at this time. -

Aug 11, 2024

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 31 of the CFTR protein (p.Arg31Leu). This variant is present in population databases (rs149353983, gnomAD 0.008%). This missense change has been observed in individuals with cystic fibrosis (PMID: 12454843, 28392015, 30888834, 31916691, 34350279). ClinVar contains an entry for this variant (Variation ID: 54087). 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) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 16339147). 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. -

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 13, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R31L variant (also known as c.92G>T), located in coding exon 2 of the CFTR gene, results from a G to T substitution at nucleotide position 92. The arginine at codon 31 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in an individual with elevated sweat chloride levels and virtually normal pulmonary and pancreatic function; however, no second CFTR alteration was identified (Zielenski J, Hum. Mutat. 1995; 5(1):43-7). In vitro protein studies show that this alteration causes a reduction in the surface expression of the CFTR protein (Jurkuvenaite A, J. Biol. Chem. 2006 Feb; 281(6):3329-34; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). 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 the available evidence, the clinical significance of this variant remains unclear. -

not provided

Uncertain:3

Mar 19, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.92G>T p.Arg31Leu variant (rs149353983; ClinVar Variation ID: 54087) is reported in patients diagnosed with cystic fibrosis. However, in one patient carrying only p.Arg31Leu and no other CFTR variant, lung and pancreatic function were evidently normal at age 24 despite pulmonary symptoms diagnosed at age 5; though sweat chloride remained elevated (Zielenski 1995). Another CF patient with pancreatic sufficiency and without pancreatitis carried this variant and a pathogenic variant with varying clinical consequences, p.Pro67Leu (Durno 2002). This variant is also reported in the CFTR2 database in seven individuals who also carry F508del (Munck 2020 and McCague 2019). However, sweat chloride ranges are in an indeterminate range (30-60 mmol/L) and CFTR2 lists this variant as of uncertain clinical consequence. This variant is only observed on eleven alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional evidence suggest that this variant reduces receptor trafficking and channel function, though data are inconsistent as to the overall magnitude of this effect (Jurkuvenaite 2006 and Raraigh 2018). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.546). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Durno C et al. Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology. 2002 Dec;123(6):1857-64. PMID: 12454843. Jurkuvenaite A et al. Mutations in the amino terminus of the cystic fibrosis transmembrane conductance regulator enhance endocytosis. J Biol Chem. 2006 Feb 10;281(6):3329-34. PMID: 16339147. McCague AF et al. Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis. Am J Respir Crit Care Med. 2019 May 1;199(9):1116-1126PMID: 30888834 Munck A et al. Phenotype of children with inconclusive cystic fibrosis diagnosis after newborn screening. Pediatr Pulmonol. 2020 Apr;55(4):918-928. PMID: 31916691. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. PMID: 29805046. Zielenski J et al. Identification of six mutations (R31L, 441delA, 681delC, 1461ins4, W1089R, E1104X) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Mutat. 1995;5(1):43-7. PMID: 7537150. -

not specified

Uncertain:1

Apr 07, 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.92G>T (p.Arg31Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251968 control chromosomes. c.92G>T has been reported in the literature as a heterozygous non-informative genotype (second allele not specified) in a 24 year old initially reported with pulmonary symptoms at age 5.7 years but virtually normal pulmonary and pancreatic functions at age 24 despite an elevated sweat chloride level (90.8 mmol/L) (example, Zielenski_1995); in compound heterozygosity with p.F508del in at-least 7 individuals with a mean sweat chloride level of 37 mmol/L in the CFTR-2 database (example, McCague_2019, Munck_2020); a non-informative genotype in the South African CF registry (SACFR) (example, Zampoli_2021). These data do not allow any conclusion about variant significance. At least three publications report conflicting experimental evidence evaluating an impact on protein function in-vitro (example, Jurkuvenalte_2006, Raraigh_2018, Bihler_2024). The most pronounced variant effect results in diminished channel activity compared to wild-type (<10% of WT) in one study (Jurkuvenalte_2006), an indeterminate level of channel activity (56% of WT) in another (Raraigh_2018) and approximately (Gt channel conductance) 22% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 18193900, 17098864, 18306312, 17235394, 17098482, 7526685, 16251901, 31036917, 38388235, 16339147, 30888834, 15536480, 31916691, 29805046, 34996830, 34583889, 34350279, 7537150). ClinVar contains an entry for this variant (Variation ID: 54087). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Lung disease, non-specific

Uncertain:1

Jun 17, 2015

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary pancreatitis

Uncertain:1

Apr 30, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

May 09, 2022

Fulgent Genetics, Fulgent Genetics

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

0.17

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;.;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.25

T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.8

L;.;.;.;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.4

N;.;.;N;.

REVEL

Uncertain

0.55

Sift

Benign

0.11

T;.;.;T;.

Sift4G

Uncertain

0.0080

D;.;.;D;.

Polyphen

0.33

B;.;.;.;.

Vest4

0.89

MVP

0.99

MPC

0.0043

ClinPred

0.091

GERP RS

1.9

Varity_R

0.27

gMVP

0.76

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over