Cystic Fibrosis (CFTR) Expanded Variant Panel

Last Literature Review: January 2025 Last Update:

Cystic fibrosis (CF) is an autosomal recessive disorder caused by variants in the CFTR gene. Age of onset, manifestations, and symptom severity vary greatly. Symptoms of classic CF include chronic sinopulmonary disease, pancreatic insufficiency, hepatic disease, prolapsed rectum, meconium ileus, obstructive azoospermia, and salt loss syndromes. Life expectancy is reduced. CFTR-related disorders are less severe and may be characterized by idiopathic pancreatitis, bilateral absence of the vas deferens, bronchiectasis, and/or nasal polyposis. These disorders typically present in adulthood and may not decrease life expectancy. Molecular testing may be used for carrier screening and diagnostic testing.

The American College of Medical Genetics (ACMG) and the American College of Obstetricians and Gynecologists (ACOG) recommend CTFR carrier screening for all couples planning a pregnancy or currently expecting. , 

ACMG now recommends carrier screening for 100 specific, pathogenic CFTR variants, an increase from the previously recommended 23 variants (known as "ACMG-23").  The Cystic Fibrosis (CFTR) Expanded Variant Panel detects 165 variants, which include the previously established 23 pathogenic CFTR variants and 69 of the 100 ACMG-recommended variants. Refer to the Variants Tested section for a complete list.

Disease Overview

Incidence and Carrier Frequency of CF
EthnicityIncidence of Classic CF Carrier Frequency
Ashkenazi Jewish1/2,3001/24
Caucasian/White1/2,5001/25
Hispanic American1/13,5001/58
African American/Black1/15,1001/61
Asian American1/35,1001/94

Genetics

Gene

CFTR

Variants

There are more than 2,000 identified variants in the CFTR gene, although most are very rare and not well characterized. CFTR is the only gene known to be causative for CF. Classic CF is caused by two severe pathogenic CFTR variants on opposite chromosomes. CFTR-related disorders are generally caused by one severe and one mild CFTR variant on opposite chromosomes.

For a full list of variants tested, see the Variants Tested table.

Inheritance

Autosomal recessive

Penetrance

  • Complete for two severe variants on opposite chromosomes
  • Incomplete when there are two pathogenic variants on opposite chromosomes and at least one is mild or a variant of varying clinical consequence (i.e., one severe and one mild variant). Such combinations may or may not cause symptoms of a CFTR-related disorder.

Test Description

All variants in the Variants Tested table are assessed.

If one copy of the R117H variant is detected, then testing for the mild 5T variant is performed. If the 5T variant is also detected, cis/trans testing is performed to determine whether the variants are on the same chromosome. The mild 5T variant, c.1210−12[5], will only be reported if either the R117H variant is detected or the individual is reported to be symptomatic.

Test Interpretation

ResultInterpretationRecommendations
No CFTR variants identifiedReduced risk for being a carrier of or affected with CFSee risk reduction in the Carrier Risk for Asymptomatic Individuals and Percentage of Patients With CF tables
1 severe CFTR variant identifiedAt least a carrier of CF and may be affected if an additional variant is present but not identified

Consider sequencing and deletion/duplication analysis if symptomatic

Offer carrier screening to relatives and reproductive partner

2 severe CFTR variants identifiedPredicted to be affected

Refer to a CF clinic for disease management

Offer carrier screening to family members and reproductive partner

2 CFTR variants detected (at least 1 mild)Increased risk for a CFTR-related disorderIf severe CF variant is identified, CF carrier screening should be offered to family members and reproductive partner

Sensitivity/Specificity

Clinical Sensitivity

Clinical sensitivity varies depending on ethnicity.

Carrier Risk for Asymptomatic Individuals Before and After a Negative Cystic Fibrosis (CFTR) Expanded Variant Panel
EthnicityVariant Detection RateCarrier Risk Before TestCarrier Risk After Negative Test
African American/Black78%1/611/275
Ashkenazi Jewish96%1/241/575
Asian American55%1/941/210
Hispanic American80%1/581/285
Caucasian/White92%1/251/300
Percentage of Patients With CF Who Have No or Only One Detectable Variant on Cystic Fibrosis (CFTR) Expanded Variant Panel
EthnicityCF Patients With No Detectable Pathogenic VariantsCF Patients With Only One Detectable Pathogenic Variant
African American/Black5%34%
Ashkenazi Jewish1%7%
Asian American20%50%
Hispanic American4%32%
Caucasian/White1%15%

Analytic Sensitivity/Specificity

99%

Limitations

  • Diagnostic errors can occur due to rare sequence variations.
  • Only CFTR variants listed in the Variants Tested table will be interrogated.

Variants Tested

CFTR Variants Tested by Cystic Fibrosis (CFTR) Expanded Variant Panel
Legacy NamecDNA NameProtein Name
M1Vc.1A>Gp.Met1Val
CFTRdele2,3 (deletion of exons 2 and 3)c.54-5940_273+10250del21kbExons 2-3del
Q39Xc.115C>Tp.Gln39X
♦ E60Xc.178G>Tp.Glu60X
♦ P67Lc.200C>Tp.Pro67Leu
♦ R75Xc.223C>Tp.Arg75X
G85Ec.254G>Ap.Gly85Glu
♦ 394delTTc.262_263delTT

p.Leu88IlefsX22

aka p.Leu88fs

405+1G>Ac.273+1G>AIntronic
405+3A>CC.273+3A>CIntronic
♦ 406-1G>Ac.274-1G>AIntronic
E92Kc.274G>Ap.Glu92Lys
E92Xc.274G>Tp.Glu92X
♦ Q98Xc.292C>Tp.Gln98X
♦ 444delAc.313delA

p.Ile105SerfsX2

aka p.Ile105fs

457TAT>Gc.325_327delTATinsG

p.Tyr109GlyfsX4

aka p.Tyr109fs

♦ D110Hc.328G>Cp.Asp110His
♦ R117Cc.349C>Tp.Arg117Cys
♦ R117Hc.350G>Ap.Arg117His
Y122Xc.366T>Ap.Tyr122X
574delAc.442delA

p.Ile148LeufsX5

aka p.Ile148fs

♦ 621+1G>Tc.489+1G>TIntronic
663delTc.531delT

p.Ile177MetfsX12

aka p.Ile177fs

G178Rc.532G>Ap.Gly178Arg
♦ 711+1G>Tc.579+1G>TIntronic
711+5G>Ac.579+5G>AIntronic
♦ 711+3A>Gc.579+3A>GIntronic
712-1G>Tc.580-1G>TIntronic
H199Yc.595C>Tp.His199Tyr
P205Sc.613C>Tp.Pro205Ser
♦ L206Wc.617T>Gp.Leu206Trp
Q220Xc.658C>Tp.Gln220X
L227Rc.680T>Gp.Leu227Arg
852del22c.722_743del

p.Gly241GlufsX13

aka p.Gly241fs

♦ 935delAc.803delA

p.Asn268IlefsX17

aka p.Asn268fs

936delTAc.805_806delAT

p.Ile269ProfsX4

aka p.Ile269fs

F312delc.935_937delTCTp.Phe312del
1078delTc.948delT

p.Phe316LeufsX12

aka p.Phe316fs

♦ G330Xc.988G>Tp.Gly330X
♦ R334Wc.1000C>Tp.Arg334Trp
I336Kc.1007T>Ap.Ile336Lys
S341Pc.1021T>Cp.Ser341Pro
♦ 1154insTCc.1021_1022dupTC

p.Phe342HisfsX28

aka p.Phe342fs

♦ R347Hc.1040G>Ap.Arg347His
♦ R347Pc.1040G>Cp.Arg347Pro
♦ R352Qc.1055G>Ap.Arg352Gln
1213delTc.1081delT

p.Trp361GlyfsX8

aka p.Trp361fs

1248+1G>Ac.1116+1G>AIntronic
1259insAc.1130dupA

p.Gln378AlafsX4

aka p.Gln378fs

♦ 1288insTAc.1155_1156dupTA

p.Asn386IlefsX3

aka p.Asn386fs

W401X(TAG)c.1202G>Ap.Trp401X
W401X(TGA)c.1203G>Ap.Trp401X
1341+1G>Ac.1209+1G>AIntronic
IVS8 5Tac.1210−125Intronic
♦ 1461ins4c.1327_1330dupGATA

p.Ile444ArgfsX3

aka p.Ile444fs

1471delAc.1340delA

p.Lys447ArgfsX2

aka p.Lys447fs

♦ A455Ec.1364C>Ap.Ala455Glu
♦ 1525-1G>Ac.1393-1G>AIntronic
S466X(TAA)c.1397C>Ap.Ser466X
♦ S466X(TAG)c.1397C>Gp.Ser466X
♦ L467Pc.1400T>Cp.Leu467Pro
1548delGc.1418delG

p.Gly473GlufsX54

aka p.Gly473fs

G480Cc.1438G>Tp.Gly480Cys
S489Xc.1466C>Ap.Ser489X
S492Fc.1475C>Tp.Ser492Phe
Q493Xc.1477C>Tp.Gln493X
♦ I507delc.1519_1521delATCp.Ile507del
♦ F508delc.1521_1523delCTTp.Phe508del
1677delTAc.1545_1546delTAp.Tyr515X
V520Fc.1558G>Tp.Val520Phe
♦ C524Xc.1572C>Ap.Cys524X
Q525Xc.1573C>Tp.Gln525X
♦ 1717-1G>Ac.1585-1G>AIntronic
1717-8G>Ac.1585-8G>AIntronic
♦ G542Xc.1624G>Tp.Gly542X
S549R(A>C)c.1645A>Cp.Ser549Arg
♦ S549Nc.1646G>Ap.Ser549Asn
♦ S549R(T>G)c.1647T>Gp.Ser549Arg
♦ G551Sc.1651G>Ap.Gly551Ser
G551Dc.1652G>Ap.Gly551Asp
Q552Xc.1654C>Tp.Gln552X
♦ R553Xc.1657C>Tp.Arg553X
♦ A559Tc.1675G>Ap.Ala559Thr
R560Kc.1679G>Ap.Arg560Lys
♦ R560Tc.1679G>Cp.Arg560Thr
♦ 1811+1.6kbA>G

c.1680-886A>G

aka c.1679+1.6kbAG

Intronic
1812-1G>Ac.1680-1G>AIntronic
1833delTc.1703delT

p.Leu568CysfsX4

aka p.Leu568fs

♦ Y569Dc.1705T>Gp.Tyr569Asp
P574Hc.1721C>Ap.Pro574His
♦ E585Xc.1753G>Tp.Glu585X
♦ 1898+1G>Ac.1766+1G>AIntronic
1898+3A>Gc.1766+3A>GIntronic
1924del7c.1792_1798delAAAACTA

p.Lys598GlyfsX11

aka p.Lys598fs

2043delGc.1911delG

p.Gln637HisfsX26

aka p.Gln637fs

2055del9>Ac.1923_1931del9insA

p.Ser641ArgfsX5

aka p.Ser641fs

2105-2117del13insAGAAAc.1973_1985del13insAGAAA

p.Arg658LysfsX4

aka p.Arg658fs

2108delAc.1976delA

p.Asn659IlefsX4

aka p.Asn659fs

2143delTc.2012delTp.Leu671X
2183delAAc.2051_2052delp.Lys684ThrfsX4
2183AA>G

c.2051_2052delinsG

aka c.2051_2delinsG

p.Lys684SerfsX38
♦ 2184delAc.2052delAp.Lys684AsnfsX38
♦ R709Xc.2125C>Tp.Arg709X
K710Xc.2128A>Tp.Lys710X
♦ 2307insAc.2175dupA

p.Glu726ArgfsX4

aka p.Glu726fs

L732Xc.2195T>Gp.Leu732X
2347delGc.2215delG

p.Val739TyrfsX16

aka p.Val739fs

♦ R764Xc.2290C>Tp.Arg764Ter
2585delTc.2453delTp.Leu818TrpfsX3 aka p.Leu818fs
E822Xc.2464G>Tp.Glu822X
♦ 2622+1G>Ac.2490+1G>AIntronic
E831Xc.2491G>Tp.Glu831X
W846Xc.2537G>Ap.Trp846X
W846X(2670TGG>TGAc.2538G>Ap.Trp846X
R851Xc.2551C>Tp.Arg851X
2711delTc.2583delT

p.Phe861LeufsX3

aka p.Phe861fs

♦ 2789+5G>Ac.2657+5G>AIntronic
♦ Q890Xc.2668C>Tp.Gln890X
2869insGc.2737_2738insGp.Tyr913X
L927Pc.2780T>Cp.Leu927Pro
2942insTc.2810dupT

p.Val938GlyfsX37

aka p.Val938fs

♦ S945Lc.2834C>Tp.Ser945Leu
3007delGc.2875delG

p.Ala959HisfsX9

aka p.Ala959fs

G970Rc.2908G>Cp.Gly970Arg
♦ 3120+1G>Ac.2988+1G>AIntronic
♦ 3120G>Ac.2988G>Ap.Gln996=
3121-1G>Ac.2989-1G>AIntronic
3171delCc.3039delC

p.Tyr1014ThrfsX9

aka p.Tyr1014fs

♦ 3199del6c.3067_3072delATAGTG

p.Ile1023_Val1024del

aka I1023_V1024del

♦ 3272-26A>Gc.3140-26A>GIntronic
L1065Pc.3194T>Cp.Leu1065Pro
♦ R1066Cc.3196C>Tp.Arg1066Cys
♦ R1066Hc.3197G>Ap.Arg1066His
L1077Pc.3230T>Cp.Leu1077Pro
♦ W1089Xc.3266G>Ap.Trp1089X
Y1092X(C>A)c.3276C>Ap.Tyr1092X
Y1092X(C>G)c.3276C>Gp.Tyr1092X
M1101Kc.3302T>Ap.Met1101Lys
E1104Xc.3310G>Tp.Glu1104X
♦ R1158Xc.3472C>Tp.Arg1158X
♦ R1162Xc.3484C>Tp.Arg1162X
♦ 3659delCc.3528delC

p.Lys1177SerfsX15

aka p.Lys1177fs

3667ins4c.3532_3535dupTCAA

p.Thr1179IlefsX17

aka p.Thr1179fs

S1196Xc.3587C>Gp.Ser1196X
W1204X(3743G>A)c.3611G>Ap.Trp1204X
♦ W1204X(3744G>A)c.3612G>Ap.Trp1204X
♦ 3791delCc.3659delC

p.Thr1220LysfsX8

aka p.Thr1220fs

3821delTc.3691delT

p.Ser1231ProfsX4

aka p.Ser1231fs

Q1238Xc.3712C>Tp.Gln1238X
♦ 3849+10kbC>Tc.3718-2477C>TIntronic
G1244Ec.3731G>Ap.Gly1244Glu
♦ 3876delAc.3744delA

p.Lys1250ArgfsX9

aka p.Lys1250fs

S1251Nc.3752G>Ap.Ser1251Asn
S1255Pc.3763T>Cp.Ser1255Pro
♦ S1255Xc.3764C>Ap.Ser1255X
3905insTc.3773dupT

p.Leu1258PhefsX7

aka p.Leu1258fs

♦ W1282Xc.3846G>Ap.Trp1282X
4005+1G>Ac.3873+1G>AIntronic
♦ N1303Kc.3909C>Gp.Asn1303Lys
Q1313Xc.3937C>Tp.Gln1313X
CFTRdele22,23c.3964-78_4242+577delExons 22-23del
C1344fsc.4025_4028dup

p.Cys1344GlyfsX16

aka p.C1344fs

G1349Dc.4046G>Ap.Gly1349Asp
4209TGTT>AAc.4077_4080delTGTTinsAA

p.Val1360delfsX3

aka p.Val1360fs

E1371Xc.4111G>Tp.Glu1371X
4382delAc.4251delA

p.Glu1418ArgfsX14

aka p.Glu1418fs

♦ Panel includes 69/100 variants recommended for carrier screening by ACMG.

aThe IVS8 5T variant, c.1210-125, will be reported when R117H is detected and in individuals who are reported to be symptomatic.

Source: Deignan 2023