ClinVar Miner

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

dbSNP: rs74551128
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Total submissions: 22
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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.
Invitae 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 2022-04-22 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 (Sheppard et al, 1995; VanGoor et al., 2014); 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, 10777368, 24416359, 7542778, 32204475, 31036917, 8886242, 22390181, 32848127)
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 2023-09-21 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

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