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

gnomAD frequency: 0.00001  dbSNP: rs74503330

Total submissions: 17

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 disorders	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826447	SCV002507414	pathogenic	CFTR-related disorders	2019-10-02	no assertion criteria provided	clinical testing