Submissions for variant NM_000492.4(CFTR):c.1364C>A (p.Ala455Glu)

dbSNP: rs74551128

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
American College of Medical Genetics and Genomics (ACMG)	RCV000007531	SCV000071390	pathogenic	Cystic fibrosis	2004-03-03	practice guideline	curation	Converted during submission to Pathogenic.
CFTR2	RCV000007531	SCV000071495	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
PharmGKB	RCV000660853	SCV000783092	drug response	ivacaftor response - Efficacy	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007531	SCV000074294	pathogenic	Cystic fibrosis	2024-01-25	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 455 of the CFTR protein (p.Ala455Glu). 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 cystic fibrosis (PMID: 2236053, 15371902, 23466340, 23974870). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7111). 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 expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 7542778, 23974870). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007531	SCV000696836	pathogenic	Cystic fibrosis	2017-02-16	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1364C>A (p.Ala455Glu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by functional studies showing the variant to result in <10% chloride conductance (Sosnay_2013). This variant was found in 4/94982 control chromosomes at a frequency of 0.0000421, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous affected individuals in the literature and is a known common disease causing mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000007531	SCV000886236	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763569	SCV000894408	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004446	SCV001163491	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007531	SCV001169478	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000007531	SCV001194086	pathogenic	Cystic fibrosis	2019-11-12	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1364C>A(A455E) is classified as pathogenic in the context of cystic fibrosis and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1364C>A(A455E) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Johns Hopkins Genomics, Johns Hopkins University	RCV000007531	SCV001430619	pathogenic	Cystic fibrosis	2020-07-24	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
GeneDx	RCV001530091	SCV001763938	pathogenic	not provided	2023-10-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced levels of mature CFTR protein and chloride transport compared to wildtype (PMID: 23891399, 7534226); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21520337, 23420618, 7534226, 9402971, 32429104, 22975760, 25489051, 22658665, 23891399, 24440181, 23378603, 23974870, 20021716, 2236053, 18456578, 29261177, 24416359, 7542778, 32204475, 31036917, 22390181, 32848127, 34996830, 10777368, 34782259, 8886242)
Ambry Genetics	RCV000007531	SCV002702901	pathogenic	Cystic fibrosis	2021-12-07	criteria provided, single submitter	clinical testing	The p.A455E pathogenic mutation (also known as c.1364C>A), located in coding exon 10 of the CFTR gene, results from a C to A substitution at nucleotide position 1364. The alanine at codon 455 is replaced by glutamic acid, an amino acid with dissimilar properties. This mutation accounts for approximately 0.3% of cystic fibrosis (CF) alleles (Corvol H et al. Transl Res, 2016 Feb;168:40-9; Brennan ML et al. J Mol Diagn, 2016 Jan;18:3-14) and is typically associated with milder manifestations of CF (Bombieri C et al. Semin Respir Crit Care Med, 2015 Apr;36:180-93). Functional in vitro studies found that cells with this pathogenic mutation maintain 6.8% chloride conduction compared to wild-type (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473003	SCV004213371	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-23	criteria provided, single submitter	clinical testing
OMIM	RCV000007531	SCV000027732	pathogenic	Cystic fibrosis	1990-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000007531	SCV001622787	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530091	SCV001744709	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001530091	SCV001806866	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001530091	SCV001927355	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001530091	SCV001952962	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001530091	SCV001964442	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826427	SCV002080580	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001826427	SCV005361582	pathogenic	CFTR-related disorder	2024-06-17	no assertion criteria provided	clinical testing	The CFTR c.1364C>A variant is predicted to result in the amino acid substitution p.Ala455Glu. This variant has been reported to be causative for cystic fibrosis in the presence of a second pathogenic allele (Kerem et al. 1990. PubMed ID: 2236053; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.