Cystic Fibrosis (CFTR) Expanded Variant Panel

Last Literature Review: April 2022 Last Update:
  • Use for carrier screening for expectant individuals or couples planning a pregnancy
  • Diagnostic testing for individuals with symptoms of classic CF
  • For use in individuals with suspected CF
  • This test is not indicated for routine carrier screening

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

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) recommended carrier screening for 23 specific pathogenic CFTR variants in all couples planning a pregnancy or currently expecting.  

Disease Overview

Incidence and Carrier Frequency of CF
Ethnicity Incidence of Classic CF  Carrier Frequency

Ashkenazi Jewish

1/2,300

1/24

Caucasian/White

1/2,500

1/25

Hispanic American

1/13,500

1/58

African American/Black

1/15,100

1/61

Asian American

1/35,100

1/94

Genetics

Gene

CFTR

Variants

There are over 2,000 identified variants in the CFTR gene, though 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 consequences (ie, 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

Result Interpretation Recommendations

No CFTR variants identified

Reduced risk for being a carrier of or affected with CF

See risk reduction in the Carrier Risk for Asymptomatic Individuals and Percentage of Patients With CF tables

One severe CFTR variant identified

At 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

Two severe CFTR variants identified

Predicted to be affected

Refer to a CF clinic for disease management

Offer carrier screening to family members and reproductive partner

Two CFTR variants detected (at least one of which is mild)

Increased risk for a CFTR-related disorder

If one of the CF variants identified is severe, 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
Ethnicity Variant Detection Rate Carrier Risk Before Test Carrier Risk After Negative Test

African American/Black

78%

1/61

1/275

Ashkenazi Jewish

96%

1/24

1/575

Asian American

55%

1/94

1/210

Hispanic American

80%

1/58

1/285

Caucasian

92%

1/25

1/300
Percentage of Patients With CF Who Have None or Only One Detectable Variant on Cystic Fibrosis (CFTR) Expanded Variant Panel
Ethnicity CF Patients With No Detectable Pathogenic Variants CF Patients With Only One Detectable Pathogenic Variant

African American/Black

5%

34%

Ashkenazi Jewish

1%

7%

Asian American

20%

50%

Hispanic American

4%

32%

Caucasian

1%

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 Name cDNA Name Protein Name

M1V

c.1A>G

p.Met1Val

CFTRdele2,3 (deletion of exons 2 and 3)

c.54-5940_273+10250del21kb

Exons 2-3del

Q39X

c.115C>T

p.Gln39X

E60X

c.178G>T

p.Glu60X

P67L

c.200C>T

p.Pro67Leu

R75X

c.223C>T

p.Arg75X

♦ G85E

c.254G>A

p.Gly85Glu

394delTT

c.262_263delTT

p.Leu88IlefsX22

aka p.Leu88fs

405+1G>A

c.273+1G>A

Intronic

405+3A>C

C.273+3A>C

Intronic

406-1G>A

c.274-1G>A

Intronic

E92K

c.274G>A

p.Glu92Lys

E92X

c.274G>T

p.Glu92X

Q98X

c.292C>T

p.Gln98X

444delA

c.313delA

p.Ile105SerfsX2

aka p.Ile105fs

457TAT>G

c.325_327delTATinsG

p.Tyr109GlyfsX4

aka p.Tyr109fs

D110H

c.328G>C

p.Asp110His

R117C

c.349C>T

p.Arg117Cys

♦ R117H

c.350G>A

p.Arg117His

Y122X

c.366T>A

p.Tyr122X

574delA

c.442delA

p.Ile148LeufsX5

aka p.Ile148fs

♦ 621+1G>T

c.489+1G>T

Intronic

663delT

c.531delT

p.Ile177MetfsX12

aka p.Ile177fs

G178R

c.532G>A

p.Gly178Arg

♦ 711+1G>T

c.579+1G>T

Intronic

711+5G>A

c.579+5G>A

Intronic

711+3A>G

c.579+3A>G

Intronic

712-1G>T

c.580-1G>T

Intronic

H199Y

c.595C>T

p.His199Tyr

P205S

c.613C>T

p.Pro205Ser

L206W

c.617T>G

p.Leu206Trp

Q220X

c.658C>T

p.Gln220X

L227R

c.680T>G

p.Leu227Arg

852del22

c.722_743del

p.Gly241GlufsX13

aka p.Gly241fs

935delA

c.803delA

p.Asn268IlefsX17

aka p.Asn268fs

936delTA

c.805_806delAT

p.Ile269ProfsX4

aka p.Ile269fs

F312del

c.935_937delTCT

p.Phe312del

1078delT

c.948delT

p.Phe316LeufsX12

aka p.Phe316fs

G330X

c.988G>T

p.Gly330X

♦ R334W

c.1000C>T

p.Arg334Trp

I336K

c.1007T>A

p.Ile336Lys

S341P

c.1021T>C

p.Ser341Pro

1154insTC

c.1021_1022dupTC

p.Phe342HisfsX28

aka p.Phe342fs

R347H

c.1040G>A

p.Arg347His

♦ R347P

c.1040G>C

p.Arg347Pro

R352Q

c.1055G>A

p.Arg352Gln

1213delT

c.1081delT

p.Trp361GlyfsX8

aka p.Trp361fs

1248+1G>A

c.1116+1G>A

Intronic

1259insA

c.1130dupA

p.Gln378AlafsX4

aka p.Gln378fs

1288insTA

c.1155_1156dupTA

p.Asn386IlefsX3

aka p.Asn386fs

W401X(TAG)

c.1202G>A

p.Trp401X

W401X(TGA)

c.1203G>A

p.Trp401X

1341+1G>A

c.1209+1G>A

Intronic

IVS8 5Ta

c.1210−125

Intronic

1461ins4

c.1327_1330dupGATA

p.Ile444ArgfsX3

aka p.Ile444fs

1471delA

c.1340delA

p.Lys447ArgfsX2

aka p.Lys447fs

♦ A455E

c.1364C>A

p.Ala455Glu

1525-1G>A

c.1393-1G>A

Intronic

S466X(TAA)

c.1397C>A

p.Ser466X

S466X(TAG)

c.1397C>G

p.Ser466X

L467P

c.1400T>C

p.Leu467Pro

1548delG

c.1418delG

p.Gly473GlufsX54

aka p.Gly473fs

G480C

c.1438G>T

p.Gly480Cys

S489X

c.1466C>A

p.Ser489X

S492F

c.1475C>T

p.Ser492Phe

Q493X

c.1477C>T

p.Gln493X

♦ I507del

c.1519_1521delATC

p.Ile507del

♦ F508del

c.1521_1523delCTT

p.Phe508del

1677delTA

c.1545_1546delTA

p.Tyr515X

V520F

c.1558G>T

p.Val520Phe

C524X

c.1572C>A

p.Cys524X

Q525X

c.1573C>T

p.Gln525X

♦ 1717-1G>A

c.1585-1G>A

Intronic

1717-8G>A

c.1585-8G>A

Intronic

♦ G542X

c.1624G>T

p.Gly542X

S549R(A>C)

c.1645A>C

p.Ser549Arg

S549N

c.1646G>A

p.Ser549Asn

S549R(T>G)

c.1647T>G

p.Ser549Arg

G551S

c.1651G>A

p.Gly551Ser

♦ G551D

c.1652G>A

p.Gly551Asp

Q552X

c.1654C>T

p.Gln552X

♦ R553X

c.1657C>T

p.Arg553X

A559T

c.1675G>A

p.Ala559Thr

R560K

c.1679G>A

p.Arg560Lys

♦ R560T

c.1679G>C

p.Arg560Thr

1811+1.6kbA>G

c.1680-886A>G

aka c.1679+1.6kbAG

Intronic

1812-1G>A

c.1680-1G>A

Intronic

1833delT

c.1703delT

p.Leu568CysfsX4

aka p.Leu568fs

Y569D

c.1705T>G

p.Tyr569Asp

P574H

c.1721C>A

p.Pro574His

E585X

c.1753G>T

p.Glu585X

♦ 1898+1G>A

c.1766+1G>A

Intronic

1898+3A>G

c.1766+3A>G

Intronic

1924del7

c.1792_1798delAAAACTA

p.Lys598GlyfsX11

aka p.Lys598fs

2043delG

c.1911delG

p.Gln637HisfsX26

aka p.Gln637fs

2055del9>A

c.1923_1931del9insA

p.Ser641ArgfsX5

aka p.Ser641fs

2105-2117del13insAGAAA

c.1973_1985del13insAGAAA

p.Arg658LysfsX4

aka p.Arg658fs

2108delA

c.1976delA

p.Asn659IlefsX4

aka p.Asn659fs

2143delT

c.2012delT

p.Leu671X

2183delAA

c.2051_2052del

p.Lys684ThrfsX4

2183AA>G

c.2051_2052delinsG

aka c.2051_2delinsG

p.Lys684SerfsX38

♦ 2184delA

c.2052delA

p.Lys684AsnfsX38

R709X

c.2125C>T

p.Arg709X

K710X

c.2128A>T

p.Lys710X

2307insA

c.2175dupA

p.Glu726ArgfsX4

aka p.Glu726fs

L732X

c.2195T>G

p.Leu732X

2347delG

c.2215delG

p.Val739TyrfsX16

aka p.Val739fs

R764X

c.2290C>T

p.Arg764Ter

2585delT

c.2453delT

p.Leu818TrpfsX3 aka p.Leu818fs

E822X

c.2464G>T

p.Glu822X

2622+1G>A

c.2490+1G>A

Intronic

E831X

c.2491G>T

p.Glu831X

W846X

c.2537G>A

p.Trp846X

W846X(2670TGG>TGA

c.2538G>A

p.Trp846X

R851X

c.2551C>T

p.Arg851X

2711delT

c.2583delT

p.Phe861LeufsX3

aka p.Phe861fs

♦ 2789+5G>A

c.2657+5G>A

Intronic

Q890X

c.2668C>T

p.Gln890X

2869insG

c.2737_2738insG

p.Tyr913X

L927P

c.2780T>C

p.Leu927Pro

2942insT

c.2810dupT

p.Val938GlyfsX37

aka p.Val938fs

S945L

c.2834C>T

p.Ser945Leu

3007delG

c.2875delG

p.Ala959HisfsX9

aka p.Ala959fs

G970R

c.2908G>C

p.Gly970Arg

♦ 3120+1G>A

c.2988+1G>A

Intronic

3120G>A

c.2988G>A

Intronic

3121-1G>A

c.2989-1G>A

Intronic

3171delC

c.3039delC

p.Tyr1014ThrfsX9

aka p.Tyr1014fs

3199del6

c.3067_3072delATAGTG

p.Ile1023_Val1024del

aka I1023_V1024del

3272-26A>G

c.3140-26A>G

Intronic

L1065P

c.3194T>C

p.Leu1065Pro

R1066C

c.3196C>T

p.Arg1066Cys

R1066H

c.3197G>A

p.Arg1066His

L1077P

c.3230T>C

p.Leu1077Pro

W1089X

c.3266G>A

p.Trp1089X

Y1092X(C>A)

c.3276C>A

p.Tyr1092X

Y1092X(C>G)

c.3276C>G

p.Tyr1092X

M1101K

c.3302T>A

p.Met1101Lys

E1104X

c.3310G>T

p.Glu1104X

R1158X

c.3472C>T

p.Arg1158X

♦ R1162X

c.3484C>T

p.Arg1162X

♦ 3659delC

c.3528delC

p.Lys1177SerfsX15

aka p.Lys1177fs

3667ins4

c.3532_3535dupTCAA

p.Thr1179IlefsX17

aka p.Thr1179fs

S1196X

c.3587C>G

p.Ser1196X

W1204X(3743G>A)

c.3611G>A

p.Trp1204X

W1204X(3744G>A)

c.3612G>A

p.Trp1204X

3791delC

c.3659delC

p.Thr1220LysfsX8

aka p.Thr1220fs

3821delT

c.3691delT

p.Ser1231ProfsX4

aka p.Ser1231fs

Q1238X

c.3712C>T

p.Gln1238X

♦ 3849+10kbC>T

c.3718-2477C>T

Intronic

G1244E

c.3731G>A

p.Gly1244Glu

3876delA

c.3744delA

p.Lys1250ArgfsX9

aka p.Lys1250fs

S1251N

c.3752G>A

p.Ser1251Asn

S1255P

c.3763T>C

p.Ser1255Pro

S1255X

c.3764C>A

p.Ser1255X

3905insT

c.3773dupT

p.Leu1258PhefsX7

aka p.Leu1258fs

♦ W1282X

c.3846G>A

p.Trp1282X

4005+1G>A

c.3873+1G>A

Intronic

♦ N1303K

c.3909C>G

p.Asn1303Lys

Q1313X

c.3937C>T

p.Gln1313X

CFTRdele22,23

c.3964-78_4242+577del

Exons 22-23del

C1344fs

c.4025_4028dup

p.Cys1344GlyfsX16

aka p.C1344fs

G1349D

c.4046G>A

p.Gly1349Asp

4209TGTT>AA

c.4077_4080delTGTTinsAA

p.Val1360delfsX3

aka p.Val1360fs

E1371X

c.4111G>T

p.Glu1371X

4382delA

c.4251delA

p.Glu1418ArgfsX14

aka p.Glu1418fs

♦ 23 variants recommended for carrier screening by ACMG/ACOG.

aThe IVS8 5T variant, c.1210-125, will be reported when R117H is detected and in individuals who are reported to be symptomatic
Additional Resources
Related Information
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Cystic Fibrosis (CFTR) Sequencing and Deletion/Duplication
Fragile X (FMR1) With Reflex to Methylation Analysis
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