rs1800120

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_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 Benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 8.89

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3485G>A	p.Arg1162Gln	missense_variant	22/27	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.3485G>A	p.Arg1162Gln	missense_variant	22/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.66-11198C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000878

AC:

AN:

250616

Hom.:

AF XY:

0.0000886

AC XY:

AN XY:

135434

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1460930

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000937

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000121

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 13, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 10, 2023	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. -

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2023	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) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 13, 2024

Variant summary: CFTR c.3485G>A (p.Arg1162Gln) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 250616 control chromosomes. 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 report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (e.g. Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 30938940, 32292813, 32026723, 38388235, 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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.8

L;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

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

GERP RS

5.8

Varity_R

0.95

gMVP

0.97

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