7-117530975-G-T

Position:

chr7-117530975-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.350G>T(p.Arg117Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,590 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R117C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1O:2

Conservation

PhyloP100: 9.52

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a topological_domain Extracellular (size 23) in uniprot entity CFTR_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117530974-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 7-117530975-G-T is Pathogenic according to our data. Variant chr7-117530975-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117530975-G-T is described in Lovd as [Pathogenic]. Variant chr7-117530975-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.350G>T	p.Arg117Leu	missense_variant	4/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.350G>T	p.Arg117Leu	missense_variant	4/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250954

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135602

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461420

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:5Uncertain:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2024	Variant summary: CFTR c.350G>T (p.Arg117Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 1.2e-05 in 250954 control chromosomes (gnomAD). c.350G>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Ferec_1995, Wallace_2003, D'Apice_2004, Raraigh_2022). Several investigators have also reported that this variant is part of a complex allele with CFTR c.2991G>C (p.Leu997Phe) in patients with cystic fibrosis (Lucarelli_2010, Lucarelli_2015, Terlizzi_2016). Clinical evaluation of patients showed that p.Leu997Phe could be associated to CFTR-RD while the p.[Arg117Leu;Leu997Phe] is associated with a mild CF phenotype (Lucarelli_2010). The c.2991G>C variant, however, is found at a much higher frequency in controls (approximately 0.0022 in the gnomAD database). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired chloride channel stability (Hammerle_2001) and impaired CFTR function (Han_2018). These data indicate that the variant in isolation may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15084222, 7541510, 11278813, 30046002, 20706124, 25910067, 12014388, 34782259, 27738188, 12829453). ClinVar contains an entry for this variant (Variation ID: 53765). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 08, 2019	CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 11, 2023	The p.R117L pathogenic mutation (also known as c.350G>T), located in coding exon 4 of the CFTR gene, results from a G to T substitution at nucleotide position 350. The arginine at codon 117 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed April 4, 2019). This mutation has been described in trans with a pathogenic mutation in individuals with a range of clinical phenotypes including: congenital bilateral absence of the vas deferens (CBAVD) with increased sweat chloride levels and no other signs of disease, mild cystic fibrosis (CF) with pancreatic sufficiency, and classic CF with pancreatic insufficiency. It has been most commonly reported as part of a complex allele p.[R117L;L997F]. When CFTR gating activity was measured on epithelial nasal cells, activity was measured at 39% of wild-type in an individual homozygous for the complex allele, while it was 19.5% in a patient compound heterozygous for a different pathogenic mutation (Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75; Terlizzi V et al. J. Med. Genet., 2017 Apr;54:224-235). In addition, the disease-causing mutation p.R117H has been described in the same codon. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 05, 2023	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 117 of the CFTR protein (p.Arg117Leu). 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 disorders (PMID: 20706124, 27738188). This variant is also known as c.482G>T (p.Arg117Leu). ClinVar contains an entry for this variant (Variation ID: 53765). 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 not expected to disrupt CFTR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 11278813, 30046002). This variant disrupts the p.Arg117 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7525450, 15482777, 21783433, 22658665, 23974870, 24586523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, flagged submission	clinical testing	Counsyl	May 21, 2018	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jun 26, 2024

The CFTR c.350G>T (p.Arg117Leu) variant has been reported in the published literature in individuals affected with cystic fibrosis (PMIDs: 7541510 (1995), 30509709 (2018), 34782259 (2021), 32483343 (2020) and LOVD (https://databases.lovd.nl/shared/)). It has been described to have varying phenotypes in different individuals from mild CF to CFTR-related diseases (see CFTR2 (https://cftr2.org/), CFTR-France (https://cftr.iurc.montp.inserm.fr/cgi-bin/home.cgi), and PMID: 38203285 (2023)). The variant was also reported in a newborn child who had a positive screen result, but was asymptomatic at 18 months of age (PMID: 12014388 (2002)). This variant having partial function may be consistent with variable clinical presentation. Functional studies have observed the variant to have reduced chloride conductance activity, less than 10% compared to the wild-type, that improved with drug modulators (PMID: 38388235 (2024) and CFTR2 (https://cftr2.org/)). In some affected individuals, this variant is part of a complex allele where it is found on the same chromosome with c.2991G>C (p.Leu997Phe) (PMIDs: 20706124 (2010), 27738188 (2016), 30577776 (2018), 32060344 (2020)), however, may not be as responsive to drug modulators (PMID: 38388235 (2024)). Other missense changes at the p.Arg117 amino acid position have been reported as pathogenic, including the well-characterized p.Arg117His variant. The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 30, 2023

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Pathogenic and reported on 06-04-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;T;.;.;T;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.79

.;N;.;.;.;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-7.0

D;N;.;.;N;.

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;T;.;.;T;.

Sift4G

Pathogenic

0.0

D;D;.;.;D;.

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.97

MutPred

0.89

.;Loss of disorder (P = 0.0494);Loss of disorder (P = 0.0494);Loss of disorder (P = 0.0494);Loss of disorder (P = 0.0494);Loss of disorder (P = 0.0494);

MVP

0.99

MPC

0.0075

ClinPred

0.96

GERP RS

5.7

Varity_R

0.72

gMVP

0.95

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