Submissions for variant NM_000492.4(CFTR):c.3705T>G (p.Ser1235Arg)

gnomAD frequency: 0.00573  dbSNP: rs34911792

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079000	SCV000110869	benign	not specified	2012-07-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029527	SCV000285004	benign	Cystic fibrosis	2025-02-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000079000	SCV000304492	likely benign	not specified		criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000079000	SCV000538671	benign	not specified	2018-09-14	criteria provided, single submitter	clinical testing	The p.Ser1235Arg variant in CFTR is classified as benign because it has been ide ntified in 0.9% (87/10124) of Ashkenazi Jewish chromosomes and 0.7% (939/125536) of European chromosomes, including 4 homozygotes, by gnomAD (http://gnomad.broa dinstitute.org). ACMG/AMP Criteria applied: BA1.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755234	SCV000602980	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing	The CFTR c.3705T>G; p.Ser1235Arg variant (rs34911792) is historically considered to be mildly pathogenic due to its prevalence in patients diagnosed with mild respiratory disorders (Rene 2011) or chronic pancreatitis (Hamoir 2013, Steiner 2011, Weiss 2005). However, genotype-phenotype studies indicate that the variant is observed at similar frequencies between affected and asymptomatic individuals (LaRusch 2014, Monaghan 2000, Rene 2011, Sosnay 2013). Functional studies also indicate no defect in CFTR maturation or chloride transport activity (Sosnay 2013, Van Goor 2014). The variant is listed in ClinVar (Variation ID: 35872) and is observed in the general population at an overall frequency of 0.5% (1,409/279,632 alleles, including 4 homozygotes) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.531). Current evidence indicates that this variant, when present with a pathogenic CFTR variant on the opposite chromosome, is not associated with classic cystic fibrosis. However, it remains uncertain whether it may contribute to the clinical phenotype in individuals with milder CFTR-related disease (e.g., an isolated presentation of pancreatitis, congenital bilateral absence of the vas deferens, or mild lung disease). References: Hamoir C et al. Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants. Digestion. 2013; 87(4):229-39. PMID: 23751316. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014; 10(7):e1004376. PMID: 25033378. Monaghan K et al. Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study. Am J Med Genet. 2000; 95(4):361-5. PMID: 11186891. Rene C et al. p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. Eur J Hum Genet. 2011; 19(1):36-42. PMID: 20717170. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. PMID: 21520337. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36. PMID: 23891399. Weiss F et al. Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut. 2005; 54(10):1456-60. PMID: 15987793.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000755234	SCV000888089	benign	not provided	2022-02-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000029527	SCV001137494	likely benign	Cystic fibrosis	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000029527	SCV001182478	likely benign	Cystic fibrosis	2019-01-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000755234	SCV001246822	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	CFTR: BS2
Illumina Laboratory Services, Illumina	RCV001163789	SCV001325863	uncertain significance	CFTR-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Johns Hopkins Genomics, Johns Hopkins University	RCV000029527	SCV001425415	benign	Cystic fibrosis	2020-04-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000029527	SCV001737318	likely benign	Cystic fibrosis	2021-06-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001801912	SCV002529715	benign	Hereditary pancreatitis	2020-10-24	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000029527	SCV002581076	uncertain significance	Cystic fibrosis	2022-07-26	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000079000	SCV005197470	benign	not specified	2024-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029527	SCV000052179	benign	Cystic fibrosis	2013-10-29	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000079000	SCV000150651	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Natera, Inc.	RCV000029527	SCV001460115	benign	Cystic fibrosis	2020-01-11	no assertion criteria provided	clinical testing
Institute of Reproductive Genetics, University of Münster	RCV001642238	SCV001860328	likely pathogenic	Obstructive azoospermia	2021-08-23	flagged submission	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003333727	SCV004041742	uncertain significance	Congenital bilateral aplasia of vas deferens from CFTR mutation	2023-10-09	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000029527	SCV004099324	uncertain significance	Cystic fibrosis	2023-10-30	no assertion criteria provided	clinical testing