7-117611637-C-T

Position:

chr7-117611637-C-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.3196C>T(p.Arg1066Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1066H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:24

Conservation

PhyloP100: 3.34

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr7-117611638-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7158.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

PP5

Variant 7-117611637-C-T is Pathogenic according to our data. Variant chr7-117611637-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7162.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117611637-C-T is described in Lovd as [Pathogenic]. Variant chr7-117611637-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3196C>T	p.Arg1066Cys	missense_variant	20/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3196C>T	p.Arg1066Cys	missense_variant	20/27	1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+4592G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250882

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

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:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461294

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726942

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000525

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000294

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:12

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2017	Variant summary: The CFTR c.3196C>T (p.Arg1066Cys) missense variant located in the ABC transporter type 1, transmembrane domain (via InterPro) involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools.This variant was found in 9/223414 control chromosomes at a frequency of 0.0000403, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). In literature, this variant is recurrently reported in CF patients, primarily in compound heterozygous state with p.Phe508del and is regarded as a severe mutation with consistent clinical and functional outcome (Fanen_1992, Fanen_1997, Sosnay_2013, Van Goor_2013, Dupuis_2015). In a large study that included CF patients from Europe and North America, the allele frequency of this variant was 0.15% (122/79,392 CF chromosomes) (Sosnay_2013). It leads to defective CFTR processing and the drug, ivacaftor, was unable to increase chloride channel function in an in vitro assay (Van Goor_2013), implicating therapeutic importance in patients carrying this variant. Other missense changes at the same residue, namely R1066H, R1066S, and R1066L, have been reported in association with CF indicating that R1066 residue is a mutational hot-spot. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 14, 2019	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 25, 2022	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 9374552) - PS3. The c.3196C>T;p.(Arg1066Cys) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID 7162; PMID: 9375855; PMID: 25697318; PMID: 27022295) -PS4. The variant is present at low allele frequencies population databases (rs78194216 – gnomAD 0.0003189%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The p.(Arg1066Cys) was detected in trans with a pathogenic variant (PMID: 9375855) - PM3. Pathogenic missense variant in this residue have been reported (Clinvar ID 7158) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 9375855 - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000492.3(CFTR):c.3196C>T(R1066C) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 23974870, 9375855 and 9374552. Classification of NM_000492.3(CFTR):c.3196C>T(R1066C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 31, 2022	ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 very strong, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 2022	The p.R1066C pathogenic mutation (also known as c.3196C>T and 3328C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3196. The arginine at codon 1066 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this mutation was identified in 21 individuals with a severe phenotype, including pancreatic insufficiency and moderate to severe pulmonary disease. Nineteen individuals were compound heterozygous for a pathogenic mutation on the other allele and two unrelated individuals were homozygous for this mutation (Casals T et al. Hum. Mutat., 1997;10:387-92). This mutation results in defective biosynthesis and processing of the CFTR protein (Fanen P et al. J. Biol. Chem., 1997 Nov;272:30563-6). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1066 of the CFTR protein (p.Arg1066Cys). This variant is present in population databases (rs78194216, gnomAD 0.006%). This missense change has been observed in individuals with cystic fibrosis or congenital absence of the vas deferens (PMID: 10923036, 11883825, 15084222, 17331079, 21520337, 23302613, 23974870). This variant is also known as 3328C>T. ClinVar contains an entry for this variant (Variation ID: 7162). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 8662892, 8702904, 9374552, 15480987, 23891399, 23974870). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.3196C>T (p.Arg1066Cys) in the CFTR gene has been reported in homozygous state in individuals affected with cystic fibrosis (Alonso MJ. et al., 2007). Experimental studies have shown that this missense change severely disrupts CFTR protein processing and biosynthesis in vitro (Van Goor F. et al., 2014). This variant is reported with the allele frequency (0.003%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. The amino acid Arginine at position 1066 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 07, 2022	In the published literature, the variant has been reported as compound heterozygous and homozygous in individuals with classic CF (PMIDs: 32539862 (2020), 9475107 (1998), 9375855 (1997), 1379210 (1992)). Additionally, several functional studies indicated this variant causes defective CFTR protein processing and abnormal chloride channel function (PMIDs: 23891399 (2014), 15480987 (2004), 9374552 (1997), 8702904 (1996)). Based on the available information, this variant is classified as pathogenic. -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 21, 2019

The CFTR c.3196C>T; p.Arg1066Cys variant (rs78194216) is reported to cause pancreatic insufficient (PI) cystic fibrosis (CF) in individuals homozygous for this variant or compound heterozygous with a second PI CF-causing variant on the opposite chromosome (CFTR2 database, Casals 1997, Liang 1998). Functional analysis shows that p.Arg1066Cys results in a nonfunctional CFTR protein (Sosnay 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 7162). It is found in the general population with an overall allele frequency of 0.003% (8/250882 alleles) in the Genome Aggregation Database. The arginine at codon 1066 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES CFTR2 database: https://cftr2.org/ Casals T et al. Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients. Hum Mutat. 1997;10(5):387-92. Liang MH et al. Cystic fibrosis in a Puerto Rican female homozygous for the R1066C mutation. J Med Genet. 1998 Jan;35(1):84-5. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

CFTR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 04, 2021

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;.;.;D;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;.;.;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.6

D;.;.;D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.99

MVP

0.99

MPC

0.015

ClinPred

1.0

GERP RS

5.7

Varity_R

0.86

gMVP

0.99

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

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