NM_000492.4(CFTR):c.3017C>A (p.Ala1006Glu) AND Cystic fibrosis

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Aug 31, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000577175.12

Allele description [Variation Report for NM_000492.4(CFTR):c.3017C>A (p.Ala1006Glu)]

NM_000492.4(CFTR):c.3017C>A (p.Ala1006Glu)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC111674472:DNase I hypersensitive sites in introns 16 and 17a of CFTR [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.3017C>A (p.Ala1006Glu)

HGVS:

NC_000007.14:g.117610547C>A
NG_016465.4:g.149764C>A
NG_056128.2:g.3601C>A
NM_000492.4:c.3017C>AMANE SELECT
NP_000483.3:p.Ala1006Glu
NP_000483.3:p.Ala1006Glu
LRG_663t1:c.3017C>A
LRG_663:g.149764C>A
LRG_663p1:p.Ala1006Glu
NC_000007.13:g.117250601C>A
NM_000492.3:c.3017C>A
P13569:p.Ala1006Glu

Protein change:

A1006E

Links:

UniProtKB: P13569#VAR_000229; dbSNP: rs397508480

NCBI 1000 Genomes Browser:

rs397508480

Molecular consequence:

NM_000492.4:c.3017C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000679036	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 18456578, 10875853
SCV000924215	CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Aug 31, 2018)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001495009	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 16, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7541510, 16189704, 20691141, 21858268, 25910067, 29805046, 30046002, 28492532
SCV002573613	CFTR-France	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	Pathogenic (Aug 31, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV002753772	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 9, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20691141, 21858268, 25910067 Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.

Castellani C, Cuppens H, Macek M Jr, Cassiman JJ, Kerem E, Durie P, Tullis E, Assael BM, Bombieri C, Brown A, Casals T, Claustres M, Cutting GR, Dequeker E, Dodge J, Doull I, Farrell P, Ferec C, Girodon E, Johannesson M, Kerem B, Knowles M, et al.

J Cyst Fibros. 2008 May;7(3):179-96. doi: 10.1016/j.jcf.2008.03.009. Review.

PubMed [citation]

PMID:: 18456578
PMCID:: PMC2810954

Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens.

Casals T, Bassas L, Egozcue S, Ramos MD, Giménez J, Segura A, Garcia F, Carrera M, Larriba S, Sarquella J, Estivill X.

Hum Reprod. 2000 Jul;15(7):1476-83.

PubMed [citation]

PMID:: 10875853

See all PubMed Citations (12)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679036.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

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

From CFTR2, SCV000924215.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001495009.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1006 of the CFTR protein (p.Ala1006Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 7541510, 16189704, 20691141, 21858268, 25910067, 29805046). ClinVar contains an entry for this variant (Variation ID: 53627). 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: 29805046, 30046002). 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 CFTR-France, SCV002573613.1

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

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

From Ambry Genetics, SCV002753772.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.V562I variant (also known as c.1684G>A), located in coding exon 13 of the CFTR gene, results from a G to A substitution at nucleotide position 1684. The p.A1006E variant (also known as c.3017C>A), located in coding exon 19 of the CFTR gene, results from a C to A substitution at nucleotide position 3017. The (TG)11-5T variant is located in intron 9 of the CFTR gene within the poly-thymidine tract, and results in decreased efficiency of exon 10 splicing. The 5T variant in trans with a pathogenic CFTR mutation, or in the homozygous state, has been associated with CFTR-related disorders, including bronchiectasis (Sosnay et al. Pediatr Clin North Am 2016;63(4):585-98), acute recurrent or chronic pancreatitis (Werlin et al. J Pediatr Gastroenterol Nutr 2015; 60(5):675-9, Masson et al. PLoS One 2013; 8(8):e73522), and congenital bilateral absence of the vas deferens (CBAVD) (Bombieri et al. J Cyst Fibros 2011;10 Suppl 2:S86-102). The p.V562I, p.A1006E, and (TG)11-5T variants have often been seen in cis and reported as part of a complex allele [(TG)11-5T;p.V562I;p.A1006E]. This complex allele is shown to segregate with disease in two families: one comprised of a pair of sisters, the other of four siblings affected with cystic fibrosis (CF) (Tomaiuolo AC et al. Clin Invest Med, 2010 Aug;33:E234-9). In a study aimed at understanding the relationship between phenotype and genotype in cystic fibrosis, the [(TG)11-5T;p.V562I;p.A1006E] complex allele was identified in trans with a pathogenic mutation in 11 patients. The majority of these individuals had a diagnosis of classic CF with pancreatic sufficiency, although CFTR-related disorders were also reported (Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75). Based on the available evidence, the [(TG)11-5T;p.V562I;p.A1006E] complex allele is classified as disease causing.

#	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

Last Updated: Sep 29, 2024

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