7-117627538-G-T

Variant names:

• chr7-117627538-G-T
• rs1800120
• NM_000492.4:c.3485G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000492.4(CFTR):​c.3485G>T​(p.Arg1162Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000789 in 1,613,148 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R1162Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (1 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:9 B:5 O:1
• Conservation: PhyloP100: 8.89
• Publications: 44 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)

ENSG00000083622 (HGNC:40145):

ACMG classification

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

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000492.4
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3485G>T	p.Arg1162Leu	missense_variant	Exon 22 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.66-11198C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3485G>T	p.Arg1162Leu	missense_variant	Exon 22 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.000671 AC: 102 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000678 AC: 170 AN: 250616 AF XY: 0.000628

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000801 AC: 1170 AN: 1460930 Hom.: 1 Cov.: 31 AF XY: 0.000812 AC XY: 590 AN XY: 726762

African (AFR) AF: 0.000120 AC: 4 AN: 33436

American (AMR) AF: 0.000291 AC: 13 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53388

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000983 AC: 1093 AN: 1111396

Other (OTH) AF: 0.000530 AC: 32 AN: 60332

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74420

African (AFR) AF: 0.0000481 AC: 2 AN: 41544

American (AMR) AF: 0.000786 AC: 12 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 67998

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00136 Hom.: 2

Bravo AF: 0.000797

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000675 AC: 82

EpiCase AF: 0.00153

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:9 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:4

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3485G>T (p.Arg1162Leu) variant has been reported in the published literature in an individual with cystic fibrosis (CF) without a second CFTR variant being identified (PMID: 27022295 (2016)). The variant has also been reported in an asymptomatic individual (PMID: 28603918 (2017), 17489851 (2007)), and in multiple individuals with non-classic CF (PMID: 12167682 (2002)) and CFTR-related disorders including pancreatitis (PMID: 15097853 (2004), 23951356 (2013), 25033378 (2014)) bronchiectasis (PMID: 17035430 (2006), 33020115 (2020)), and CBAVD (PMID: 16481891 (2006)). Functional studies indicate this variant does not affect the quantity of CFTR protein, and the chloride conductance was measured at 130% that of the wild type (PMID: 23974870 (2013)). This variant is not associated with classic CF but may be associated with mild symptoms or a CF-related disorder when a CF-causing mutation is present on the opposite chromosome (see http://www.cftr2.org, PMID: 23974870 (2013), 25824995 (2015)). The frequency of this variant in the general population, 0.0037 (10/2668 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: PM5, PS3:Moderate, PS4:Moderate -

Mar 13, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 30, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classified as a non-CF-causing variant in a well curated database, however, may cause CFTR-RD in some cases (CFTR2); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27022295, 16481891, 23951356, 12167682, 18687795, 11788090, 19202204, 26474805, 23974870, 25824995, 17035430, 17594398, 21804385, 30230192, 18716917, 20812883, 27583671, 10571949, 36529661, 34405919, 34996830, D'Alcamo2022[CaseReport], 28603918, Andelkovic2018[CaseReport], 36670555, 33020115, 38388235, 38493004, 33572515, 37389024, 37253358, 37628659, Atli2023[CaseReport], 34949556, 35626323) -

Cystic fibrosis Uncertain:2 Benign:3

Nov 22, 2017

Counsyl

Significance: Likely benign

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. -

Feb 27, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 27, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1162L variant (also known as c.3485G>T), located in coding exon 22 of the CFTR gene, results from a G to T substitution at nucleotide position 3485. The arginine at codon 1162 is replaced by leucine, an amino acid with dissimilar properties. This variant has been observed with a pathogenic mutation and other CFTR alterations in individuals described with atypical cystic fibrosis, and reportedly asymptomatic individuals, but specific clinical information was limited (Groman JD et al. N Engl J Med. 2002;347(6):401-407; Claustres M et al. Hum Mutat. 2017;38(10):1297-1315). This variant has been detected in both pancreatitis patients and controls in CFTR pancreatitis association studies (Casals T et al. Pancreas. 2004;28(4):374-379; Tzetis M et al Clin Genet. 2007; 71(5):451-457; Cohn JA et al. Hum Mutat. 2005; 26(4):303-307; Giefer MJ et al. J Pediatr. 2017;186:95-100). Functional studies found this alteration resulted in conductance of chloride similar to wild type; in addition, this alteration was identified in trans with a pathogenic mutation two times in fathers of children with cystic fibrosis (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). In another study, transfected cells exhibited protein processing and expression at near normal levels compared to wild type (Salinas DB et al. J. Cyst. Fibros., 2015 Nov;14:714-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence, this variant is unlikely to be causative of classic CF; however, its clinical contribution to the development of a CFTR-related disorder is uncertain. -

CFTR-related disorder Pathogenic:1 Uncertain:1 Other:1

Mar 26, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as other and reported on 04-28-2016 by Lab or GTR ID 500110. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

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

Jun 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3485G>T, p.Arg1162Leu variant (rs1800120) has not been associated with classic cystic fibrosis (Fanen 1992, Narzi 2007, Salinas 2016, Sosnay 2013, see link to CFTR database), but is found in several individuals with CFTR-related disorders, such as bronchiectasis and chronic pancreatitis (Casals 2004, Groman 2002, Lazaro 1999, Ziedalski 2006). This variant is listed in ClinVar (Variation ID: 256253), and is found in the general population with an overall allele frequency of 0.070% (198/282012 alleles) in the Genome Aggregation Database. The variant is enriched in pancreatitis patients tested by ARUP Laboratories compared to the general population (Genome Aggregation Database), with an odds ratio of 2.0 (95 percent CI: 1.2 to 3.4, adjusted p-value: 0.04). The arginine at position 1162 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.944). Although the p.Arg1162Leu variant is not expected to cause classical cystic fibrosis, when paired with a second pathogenic CFTR variant on the opposite chromosome, the p.Arg1162Leu variant may contribute to CFTR-related disorders, such as pancreatitis. References: Link to CFTR database: http://cftr.org/ Casals T et al. Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? Pancreas. 2004; 28(4):374-9. PMID: 15097853. Fanen P et al. Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics. 1992; 13(3):770-6. PMID: 1379210. Groman J et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002; 347(6):401-7. PMID: 12167682. Lazaro C et al. Missense mutations in the cystic fibrosis gene in adult patients with asthma. Hum Mutat. 1999; 14(6):510-9. PMID: 10571949. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007; 72(1):39-46. PMID: 17594398. Salinas D et al. Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. PLoS One. 2016; 11(5):e0155624. PMID: 27214204. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870. Ziedalski T et al. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest. 2006; 130(4):995-1002. PMID: 17035430. -

not specified Benign:2

Feb 05, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.3485G>T (p.Arg1162Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 253674 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00071 vs 0.013), allowing no conclusion about variant significance. c.3485G>T has been widely reported in the literature in asymptomatic compound heterozygotes with non-informative genotypes such as another benign/non-CF causing variant or another reported pathogenic CF-causing variant, as a sole variant in a non-informative genotype in settings of CFTR-RD, and in settings of indeterminate newborn screening (example, Claustres_2017, Minso_2020, Sosnay_2013). The fact that this variant was reported among 6 non-affected fathers harboring this variant with another CFTR-causing variant in trans supports the lack of association or non-penetrance of this variant within settings of infertility (Sosnay_2013). Additionally, numerous studies spanning over a decade (1992-2010) predating the ones cited above cite the variant as a polymorphism. These data do not allow any conclusion about variant significance. Practice guidelines aimed at developing international consensus have listed this variant among non-CF causing variation while not including this among CFTR variants with varying or indeterminate clinical consequences (Girardet_2015). This is further supported by the conclusions reported in prominent databases such as CFTR2, which report this variant as having no clinical consequence in the settings of CF. To our knowledge, no conclusive experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments ranging from Pathogenic to VUS and Benign, some of whom cite overlapping evidence utilized in the context of this evaluation. Based on the lack of firm/conclusive evidence supporting an actionable outcome following a cross-sectional review of literature spanning over 3 decades as outlined above, the variant was classified as benign in the context of Cystic Fibrosis and its associated phenotypes. -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Obstructive azoospermia Uncertain:1

Dec 21, 2021

Institute of Reproductive Genetics, University of Münster

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	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.
PhyloP100		8.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.0	D;.;.;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.98	D;.;.;.;.
Vest4		0.97
MVP		1.0
MPC		0.015
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.94
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800120; hg19: chr7-117267592;