rs397508686

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_000492.4(CFTR):c.413_415dupTAC(p.Leu138dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. H139H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CFTR
NM_000492.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:9O:1

Conservation

PhyloP100: 1.64

Publications

11 publications found

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 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)

CFTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 uncertain in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000492.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 7-117531036-C-CCTA is Pathogenic according to our data. Variant chr7-117531036-C-CCTA is described in ClinVar as Pathogenic. ClinVar VariationId is 53905.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.413_415dupTAC	p.Leu138dup	disruptive_inframe_insertion	Exon 4 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.413_415dupTAC	p.Leu138dup	disruptive_inframe_insertion	Exon 4 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250744

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461526

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111846

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:7Other:1

Apr 08, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.413_415dupTAC pathogenic mutation (also known as p.L138dup), located in coding exon 4 of the CFTR gene, results from an in-frame duplication of TAC at nucleotide positions 413 to 415. This results in the duplication of an extra residue between codons 138 and 139. In our laboratory, this variant has been detected in trans with a pathogenic mutation in CFTR in an individual with intermediate sweat chloride levels (Ambry internal data). In an analysis of 40 CFTR mutations in Russian cystic fibrosis (CF) patients, this variant (reported as L138ins) was detected in 1.8% of the chromosomes (Adyan TA et al. Russ J Genet, 2018 Oct;54:1235-1244). This mutation was reported in a Polish male with congenital bilateral absence of the vas deferens (CBAVD) in conjunction with a 5T allele (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). This alteration was also described in an individual with CF in conjunction with the c.3717+12191C>T mutation; however, the phase is unclear (Behar DM et al. Mol Genet Genomic Med, 2017 May;5:223-236). Based on internal structural analysis, this pathogenic variant is anticipated to result in a significant decrease in structural stability (Liu F et al. Cell, 2017 Mar;169:85-95.e8). In addition, human CF bronchial epithelial (CFBE) cells stably expressing this mutation (reported as L138ins) had only 1.6% of CFTR function, compared to cells expressing wild-type CFTR protein (Han ST et al. JCI Insight, 2018 Jul;3:). Furthermore, the duplication has an overall frequency of approximately 0.0004% (1/250744) in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.413_415dup, results in the insertion of 1 amino acid(s) of the CFTR protein (p.Leu138dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752803445, gnomAD 0.004%). This variant has been observed in individual(s) with CFTR-related conditions (PMID: 9272157, 16189704, 28546993, 30548586). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 546insCTA and c.411_412insCTA. ClinVar contains an entry for this variant (Variation ID: 53905). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CFTR function (PMID: 30046002). For these reasons, this variant has been classified as Pathogenic. -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant was identified in 4 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3_STR, PM4_SUP, PP4 -

Feb 21, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CFTR c.413_415dupTAC (p.Leu138dup) results in an in-frame duplication that is predicted to duplicate 1 amino acids into the encoded protein. The variant allele was found at a frequency of 4e-06 in 250744 control chromosomes. c.413_415dupTAC has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Behar_2017, Guo_2018, McGinniss_2005, Petrova_2019, Walkowiak_2001). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant confers residual function 1.6% of wild-type (Han_2018). The following publications have been ascertained in the context of this evaluation (PMID: 9272157, 11589722, 16189704, 28546993, 30046002, 30548586, 30558651).ClinVar contains an entry for this variant (Variation ID: 53905). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 29, 2019

North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria Codes: PM2 PM3_VStr PM4 -

Aug 31, 2018

CFTR2

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:research

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Feb 25, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PS4_Moderate, PM2, PM3, PM4, PP5 -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Dec 28, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=34/66

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over