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

dbSNP: rs397508480

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000577175	SCV000924215	pathogenic	Cystic fibrosis	2018-08-31	reviewed by expert panel	research
Baylor Genetics	RCV001004287	SCV001163163	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577175	SCV001495009	uncertain significance	Cystic fibrosis	2022-09-16	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582546	SCV001821277	uncertain significance	not specified	2021-08-16	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3017C>A (p.Ala1006Glu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251148 control chromosomes. c.3017C>A has been reported in the literature in individuals affected with Cystic Fibrosis (example, Ferec_1995, Alonso_2007, McGinniss_2005, Tomaiuolo_2010, Lucarelli_2015). In several ascertainments, we identified a co-occurrence in cis with another pathogenic variant (CFTR 5T-TG11), providing supporting evidence for a benign role. This variant has also been frequently reported in cis with p.Val562Ile and the 5T-TG11 haplotype (example, Alonso_2007, McGinniss_2005, Tomaiuolo_2010, Lucarelli_2015). However, we have not identified conclusive evidence supporting the pathogenicity of p.Val562Ile in isolation, therefore, the clinical outcome of this triple complex of 5T-TG11, p.Ala1006Glu and p.Val562Ile remains uncertain. At-least two publications report experimental evidence evaluating an impact on protein function in isolation. The most pronounced variant effect results in <10% of normal CFTR activity (example, Han_2018, Raraigh_2018). One clinical diagnostic laboratory and the CFTR2 database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The CFTR2 database classifies the variant as classified the variant as pathogenic and the clinical diagnostic laboratory classified the variant as uncertain significance. Overlapping but not identical evidence utilized in the context of this evaluation have been cited by the clinical diagnostic laboratory submitter. Based on the evidence outlined above, the variant in isolation was classified as VUS-possibly pathogenic.
CFTR-France	RCV000577175	SCV002573613	pathogenic	Cystic fibrosis	2021-08-31	criteria provided, single submitter	curation
Ambry Genetics	RCV000577175	SCV002753772	pathogenic	Cystic fibrosis	2017-03-09	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV003159093	SCV003853092	pathogenic	not provided	2024-05-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as c.3149C>A; This variant is associated with the following publications: (PMID: 18456578, 7541510, 34996830, 21858268, 32060344, 20691141, 35032736, 30888834, 29805046, 17331079, 35698092, 15084222, 25192979, 16189704, 10875853, 25910067, 30046002, 34782259, 30134826)
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577175	SCV000679036	not provided	Cystic fibrosis		no assertion provided	literature only