NM_000492.4:c.350G>T

Variant names:

• chr7-117530975-G-T
• rs78655421
• NM_000492.4:c.350G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_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. R117H) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1 O:2
• Conservation: PhyloP100: 9.52
• Publications: 694 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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117530975-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7109.Status of the report is practice_guideline, 4 stars.
• 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, 0.98
• PP5: Variant 7-117530975-G-T is Pathogenic according to our data. Variant chr7-117530975-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.350G>T	p.Arg117Leu	missense	Exon 4 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.350G>T	p.Arg117Leu	missense	Exon 4 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.350G>T	p.Arg117Leu	missense	Exon 4 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.350G>T	p.Arg117Leu	missense	Exon 4 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250954 AF XY: 0.00000737

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461420 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727018

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000224 AC: 1 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111742

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:5 Uncertain:1 Other:1

Feb 08, 2024

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 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.

May 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.

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Sep 11, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 08, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information.

May 29, 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.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. 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 allele was found at a frequency of 1.2e-05 in 250954 control chromosomes. c.350G>T has been observed in individual(s) 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 p.Leu997Phe variant, however, is found at a much higher frequency in controls (approximately 0.0022 in the gnomAD database). A different variant affecting the same codon has been classified as likely pathogenic/pathogenic by our lab (c.349C>G, p.Arg117Gly), supporting the critical relevance of codon 117 to CFTR protein function. Multiple publications report experimental evidence evaluating an impact on protein function (Hammerle_2001, Han_2018, Bihler_2024). The most pronounced variant effect resulted in approximately 12% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 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 pathogenic.

not provided Pathogenic:1

Nov 16, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 significantly reduced chloride conductance activity, approximately 12% compared to the wild-type, that improved with drug modulators to approximately 54% activity (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)) and was shown to have approximately 3% baseline conductance improved to 18% with 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, 0.000023 (3/128902 chromosomes (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

Sep 30, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.79	N
PhyloP100		9.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.89		Loss of disorder (P = 0.0494)
MVP		0.99
MPC		0.0075
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.72
gMVP		0.95
Mutation Taster		=2/98	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: rs78655421; hg19: chr7-117171029;