rs1800120

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr7-117627538-G-A
• chr7-117627538-G-C
• chr7-117627538-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PP2 PP3_Strong

The NM_000492.4(CFTR):​c.3485G>A​(p.Arg1162Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,030 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1162L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:13
• 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: Likely_pathogenic. The variant received 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3485G>A	p.Arg1162Gln	missense_variant	Exon 22 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.66-11198C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3485G>A	p.Arg1162Gln	missense_variant	Exon 22 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000878 AC: 22 AN: 250616 AF XY: 0.0000886

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1460930 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 726762

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

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39634

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86230

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53388

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111396

Other (OTH) AF: 0.0000829 AC: 5 AN: 60332

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74292

African (AFR) AF: 0.000121 AC: 5 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.000121

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:5

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2017

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. -

Feb 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1162Q variant (also known as c.3485G>A), located in coding exon 22 of the CFTR gene, results from a G to A substitution at nucleotide position 3485. The arginine at codon 1162 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in one individual with frequent pneumonia who had normal pancreatic function and sweat chloride levels; this individual did not have a second CFTR alteration (Strandvik B et al. Genet. Test., 2001;5:235-42). R1162 is located at the hinge region of the CFTR protein and may also act as an anchor (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). However, functional studies of a different variant at the same position (p.R1162L) demonstrated normal CFTR protein processing and chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). This amino acid position is highly conserved in available vertebrate species. In addition, p.R1162Q is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Sep 27, 2022

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 glutamine, which is neutral and polar, at codon 1162 of the CFTR protein (p.Arg1162Gln). This variant is present in population databases (rs1800120, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis and/or cystic fibrosis (PMID: 11788090, 30938940, 32026723). ClinVar contains an entry for this variant (Variation ID: 555228). 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. 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. -

Sep 13, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR c.3485G>A has been identified as a single heterozygous variant in two individuals with features of cystic fibrosis, but not a classic cystic fibrosis phenotype. This CFTR variant (rs1800120) is rare (<0.1%) in a large population dataset (gnomADv2.1.1: 25/282012 total alleles; 0.009%; no homozygotes) and has been reported in ClinVar (Variation ID: 555228). Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the second predicts that it would be tolerated. The arginine residue at this position is evolutionarily conserved across all species assessed. We consider the clinical significance of CFTR c.3485G>A to be uncertain at this time. -

not provided Uncertain:5

Jul 19, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 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.3485G>A; p.Arg1162Gln variant (rs1800120) is reported in the literature in individuals with cystic fibrosis and pancreatitis (Atag 2019, Banjar 2020, Monaghan 2000) and at least one individual with atypical cystic fibrosis (Strandvik 2001). This variant is reported in ClinVar (Variation ID: 555228), and is found in the general population with an overall allele frequency of 0.0089% (25/282012 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.812). Additionally, another variant at this codon (c.3485G>T, p.Arg1162Leu) has been reported in individuals with CFTR-related disorders, such as bronchiectasis and chronic pancreatitis, and is considered mildly pathogenic (Casals 2004, Groman 2002, Lazaro 1999, Ziedalski 2006). However, given the limited clinical data and lack of functional data, the significance of this variant is uncertain at this time. References: Atag E et al. Novel mutations and deletions in cystic fibrosis in a tertiary cystic fibrosis center in Istanbul. Pediatr Pulmonol. 2019 Jun;54(6):743-750. PMID: 30938940. Banjar HH et al. Genotype patterns for mutations of the cystic fibrosis transmembrane conductance regulator gene: a retrospective descriptive study from Saudi Arabia. Ann Saudi Med. 2020 Jan-Feb;40(1):15-24. PMID: 32026723. Casals T et al. Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? Pancreas. 2004; 28(4):374-9. PMID: 15097853. 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. Monaghan KG et al. Mutation analysis of the cystic fibrosis and cationic trypsinogen genes in patients with alcohol-related pancreatitis. Am J Med Genet. 2000 Sep 11;94(2):120-4. PMID: 10982968. Strandvik B et al. Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations. Genet Test. 2001 Fall;5(3):235-42. PMID: 11788090. 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. -

Mar 27, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with features of cystic fibrosis who also harbored second CFTR variants, but familial segregation and additional clinical information was not provided (Banjar et al., 2020); Observed in an individual with alcohol-related pancreatitis and an individual with frequent pneumonias, pancreatic sufficiency, and a normal sweat chloride test (Monaghan et al., 2000; Strandvik et al., 2001); 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: 34426522, 23974870, 25033378, 32292813, 34996830, 30938940, 10982968, 32026723, 11788090) -

Jan 14, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Feb 09, 2024

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.3485G>A (p.Arg1162Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 250616 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (8.8e-05 vs 0.013), allowing no conclusion about variant significance. c.3485G>A has been reported in the literature in individuals affected with Cystic Fibrosis and pancreatitis, without strong evidence for causality (example: Strandvik_2001, Monaghan_2000, Atag_2019, Benjar_2020, Benjar_2020). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30938940, 32026723, 32292813, 10982968, 11788090). ClinVar contains an entry for this variant (Variation ID: 555228). Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorder Uncertain:1

Jul 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.3485G>A variant is predicted to result in the amino acid substitution p.Arg1162Gln. This variant has been reported in the compound heterozygous state in an individual with cystic fibrosis (Banjar et al. 2020. PubMed ID: 32026723). This variant has also been reported in the heterozygous state in an individual with cystic fibrosis, an individual with frequent pneumonias who had normal pancreatic function and sweat chloride levels, and in an individual with pancreatitis however, the presence of a second CFTR variant was either unknown or not specified in any of these individuals (Monaghan et al. 2000. PubMed ID: 10982968; Strandvik et al. 2001. PubMed ID: 11788090; Atag et al. 2019. PubMed ID: 30938940). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Feb 14, 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	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.8	L;.;.;.;.
PhyloP100		8.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D;.;.;D;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.47	P;.;.;.;.
Vest4		0.99
MutPred		0.90		Loss of MoRF binding (P = 0.0224);.;.;.;.;
MVP		0.99
MPC		0.016
ClinPred		0.31	T
GERP RS		5.8
Varity_R		0.95
gMVP		0.97
Mutation Taster		=4/96	disease causing

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: rs1800120; hg19: chr7-117267592;