ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3752G>A (p.Ser1251Asn)

gnomAD frequency: 0.00001  dbSNP: rs74503330
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000007638 SCV000071525 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
PharmGKB RCV000211301 SCV000268392 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506301 SCV000601106 pathogenic not provided 2017-04-04 criteria provided, single submitter clinical testing
Mendelics RCV000007638 SCV000886262 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780175 SCV000917224 pathogenic not specified 2017-12-11 criteria provided, single submitter clinical testing Variant summary: The CFTR c.3752G>A (p.Ser1251Asn) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/240702 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous CF patients worldwide and functional studies showed variant with defective channel opening and chloride transport (<10% normal CFTR). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
CFTR-France RCV000007638 SCV001169364 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV000007638 SCV001182617 pathogenic Cystic fibrosis 2022-09-21 criteria provided, single submitter clinical testing The p.S1251N pathogenic mutation (also known as c.3752G>A and 3884G>A), located in coding exon 23 of the CFTR gene, results from a G to A substitution at nucleotide position 3752. The serine at codon 1251 is replaced by asparagine. This mutation was first reported in two individuals with pancreatic insufficiency (PI), severe pulmonary disease, and gastrointestinal disease; both individuals carried the p.F508C alteration in cis and the p.F508del mutation in trans (K&auml;lin N, et al. Hum Mutat. 1992; 1(3):204-10). This mutation is associated with elevated sweat chloride levels, lung disease, and PI; in addition, a functional study found this mutation resulted in significantly decreased rates of chloride conductance (Sosnay PR, et al. Nat Genet. 2013; 45(10):1160-7, Supplementary Table). Based on the supporting evidence, p.S1251N is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV000007638 SCV001193914 pathogenic Cystic fibrosis 2019-12-07 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.3752G>A(S1251N) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3752G>A(S1251N) 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.
Invitae RCV000007638 SCV001588871 pathogenic Cystic fibrosis 2023-07-29 criteria provided, single submitter clinical testing This missense change has been observed in individuals with cystic fibrosis (PMID: 1284535, 17481968, 23974870, 26989879). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 22293084). 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. ClinVar contains an entry for this variant (Variation ID: 7217). This variant is present in population databases (rs74503330, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1251 of the CFTR protein (p.Ser1251Asn).
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000007638 SCV002507330 pathogenic Cystic fibrosis 2019-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV003466832 SCV004215213 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-01-13 criteria provided, single submitter clinical testing
OMIM RCV000007638 SCV000027839 pathogenic Cystic fibrosis 1993-01-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000506301 SCV001743351 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000506301 SCV001952322 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000506301 SCV001975807 pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV001826447 SCV002075880 pathogenic CFTR-related disorder 2017-03-17 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001826447 SCV002507414 pathogenic CFTR-related disorder 2019-10-02 no assertion criteria provided clinical testing

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