ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3752G>A (p.Ser1251Asn) (rs74503330)

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Total submissions: 12
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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 2018-03-23 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
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 RCV001021052 SCV001182617 pathogenic Inborn genetic diseases 2019-09-04 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 <span style="background-color:initial">pancreatic insufficiency (PI), severe pulmonary disease, and gastrointestinal disease; both individuals carried the p.F508C alteration<span style="background-color:initial"> in cis and the p.F508del mutation in trans (<span style="background-color:initial">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 (<span style="background-color:initial">Sosnay PR, et al. Nat Genet. 2013; 45(10):1160-7, <span style="background-color:initial">Supplementary Table)<span style="background-color:initial">. <span style="background-color:initial">Based on the supporting evidence, <span style="background-color:initial">p.S1251N <span style="background-color:initial">is interpreted as a disease-causing mutation.
Myriad Women's Health, 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 2020-04-18 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1251 of the CFTR protein (p.Ser1251Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs74503330, ExAC 0.006%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 26989879, 17481968, 23974870,1284535). ClinVar contains an entry for this variant (Variation ID: 7217). This variant has been reported to affect CFTR protein function (PMID: 22293084). For these reasons, this variant has been classified as Pathogenic.
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
Human Genetics - Radboudumc,Radboudumc RCV000506301 SCV001952322 pathogenic not provided no assertion criteria provided clinical testing

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