NM_000492.4(CFTR):c.3415A>G (p.Ile1139Val) AND Cystic fibrosis

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Sep 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001857385.15

Allele description [Variation Report for NM_000492.4(CFTR):c.3415A>G (p.Ile1139Val)]

NM_000492.4(CFTR):c.3415A>G (p.Ile1139Val)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.3415A>G (p.Ile1139Val)

HGVS:

NC_000007.14:g.117614660A>G
NG_016465.4:g.153877A>G
NM_000492.4:c.3415A>GMANE SELECT
NP_000483.3:p.Ile1139Val
NP_000483.3:p.Ile1139Val
LRG_663t1:c.3415A>G
LRG_663:g.153877A>G
LRG_663p1:p.Ile1139Val
NC_000007.13:g.117254714A>G
NM_000492.3:c.3415A>G

Protein change:

I1139V

Links:

dbSNP: rs397508556

NCBI 1000 Genomes Browser:

rs397508556

Molecular consequence:

NM_000492.4:c.3415A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

Recent activity

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14q240 - Chromosomal Variation in Man
14q240 - Chromosomal Variation in Man
AP-1 complex subunit gamma-like 2 isoform 2 [Homo sapiens]
AP-1 complex subunit gamma-like 2 isoform 2 [Homo sapiens]
gi|541862241|ref|NP_001269403.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001181692	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 8, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17003641, 20021716, 26900683, 27171515, 7881429, 9345100, 9804160 Citation Link,
SCV002168891	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 25, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7881429, 17003641, 20021716, 27171515, 28801929, 9804160, 28492532
SCV002573850	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2022)	unknown	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001181692

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 8, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV002168891

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 25, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002573850

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 5, 2022)

unknown

curation

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	4	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Applicability and Efficiency of NGS in Routine Diagnosis: In-Depth Performance Analysis of a Complete Workflow for CFTR Mutation Analysis.

Pagin A, Devos A, Figeac M, Truant M, Willoquaux C, Broly F, Lalau G.

PLoS One. 2016;11(2):e0149426. doi: 10.1371/journal.pone.0149426.

PubMed [citation]

PMID:: 26900683
PMCID:: PMC4762772

CFTR gene mutations in men with bilateral ejaculatory-duct obstruction and anomalies of the seminal vesicles.

Meschede D, Dworniczak B, Behre HM, Kliesch S, Claustres M, Nieschlag E, Horst J.

Am J Hum Genet. 1997 Nov;61(5):1200-2. No abstract available.

PubMed [citation]

PMID:: 9345100
PMCID:: PMC1716026

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV001181692.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.I1139V variant (also known as c.3415A>G), located in coding exon 21 of the CFTR gene, results from an A to G substitution at nucleotide position 3415. The isoleucine at codon 1139 is replaced by valine, an amino acid with highly similar properties. This variant was originally reported in a healthy father of a child who had cystic fibrosis with elevated sweat chloride levels, pancreatic sufficiency, and respiratory disease. The mother was heterozygous for a nonsense variant; however, analysis was not performed in the child (Teng H et al. Hum. Mol. Genet., 1994 Dec;3:2249-50). This alteration was identified in multiple individuals with pancreatitis who carried a pathogenic variant (Keiles S et al. Pancreas, 2006 Oct;33:221-7; Pagin A et al. PLoS One, 2016 Feb;11:e0149426; Ambry internal data). However, this variant has also been detected in trans with a pathogenic mutation in unrelated individuals with normal sweat chloride levels (Ambry internal data). In a functional study, I1139V did not affect protein maturation, but reduced cAMP-activated whole cell chloride currents (Vankeerberghen A et al. FEBS Lett., 1998 Oct;437:1-4). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002168891.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1139 of the CFTR protein (p.Ile1139Val). This variant is present in population databases (rs397508556, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 7881429, 17003641, 20021716, 27171515, 28801929). ClinVar contains an entry for this variant (Variation ID: 53736). 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 not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 9804160). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002573850.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	curation	PubMed (1)

Description

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, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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