Submissions for variant NM_000492.4(CFTR):c.650A>G (p.Glu217Gly)

gnomAD frequency: 0.00335  dbSNP: rs121909046

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000007660	SCV000267252	uncertain significance	Cystic fibrosis	2016-03-18	criteria provided, single submitter	reference population
Illumina Laboratory Services, Illumina	RCV001095295	SCV000466505	likely benign	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007660	SCV000562306	benign	Cystic fibrosis	2024-02-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586415	SCV000601129	uncertain significance	not provided	2021-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506350	SCV000697040	uncertain significance	not specified	2024-08-05	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.650A>G (p.Glu217Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0047 in 259928 control chromosomes, including 29 homozygotes (gnomAD and publications); particularly at a frequency of 0.0095 within the East Asian subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing CFTR-related diseases phenotype (0.0095 vs 0.013), suggesting that the variant may be a benign polymorphism. c.650A>G has been reported in the literature in individuals affected with CFTR-Related Diseases such as Cystic Fibrosis (CF), chronic pancreatitis and CBAVD (example: Audrezet_2002, Guan_2018, Petrova_2020, Luo_2021), but also in many controls (example: Kars_2021). These reports do not provide unequivocal conclusions about association of the variant with CFTR-Related Diseases. Munck et al (2019) report a patient with inconclusive CF diagnosis harboring a second allele of F508del, with sweat chloride levels < 30 mmol/L. Nevertheless, Petroval et al (2020) report another patient with F508del in trans who had a diagnosis of CF, with sweat chloride levels of 63 mmol/L. CFTR-France database reports this variant in two asymptomatic compound heterozygotes with a CF-causing variant in trans. Functional studies report significantly decreased chloride channel activity associated with the variant when transfected into CHO-K1 and BHK cells (Hammerl_2001, Lee_2003, Chang_2018, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 15463840, 11938439, 16596947, 38388235, 29307731, 17539902, 29997923, 11278813, 34426522, 20879059, 26089335, 31882543, 12952861, 22483971, 32777524, 22664493, 16126774, 31916691, 32429104, 31245908, 18304229, 21520337, 26436105, 11589722, 27706244, 31423445, 17516627, 24586523). ClinVar contains an entry for this variant (Variation ID: 7238). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Eurofins Ntd Llc (ga)	RCV000586415	SCV000700761	uncertain significance	not provided	2018-07-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000007660	SCV001137468	uncertain significance	Cystic fibrosis	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007660	SCV001187527	benign	Cystic fibrosis	2018-03-02	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Genome-Nilou Lab	RCV000007660	SCV001737307	uncertain significance	Cystic fibrosis	2021-06-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000586415	SCV002540889	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing	BS1, BS2, PM3_strong, PS3
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007660	SCV002573926	uncertain significance	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_MOD, PM3, BS2, BP2
CeGaT Center for Human Genetics Tuebingen	RCV000586415	SCV004158946	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	CFTR: BS2
GeneDx	RCV000586415	SCV004169825	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Observed with CF-causing variants on the opposite allele (in trans) in asymptomatic individuals (Claustres et al., 2017); Observed in the homozygous state in healthy adult individuals tested at GeneDx and in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 23951356, 29058463, 34426522, 17516627, 21520337, 34405919, 29307731, 15463840, 11589722, 16126774, 11938439, 22664493, 26089335, 34996830, 16596947, 20558957, 17539902, 10922396, 22483971, 32777524, 32429104, 29173301, 24586523, 12952861, 27706244, 26436105, 20879059, 29997923, 18304229, 31916691, 11278813, 28603918, 31882543)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586415	SCV004563253	uncertain significance	not provided	2023-11-27	criteria provided, single submitter	clinical testing	The CFTR c.650A>G; p.Glu217Gly variant (rs121909046) is reported in the literature in patients affected with congenital bilateral absence of vas deferens (Cheng 2022, Fang 2022, Li 2012, Luo 2021), bronchiectasis (Guan 2018, Lee 2003), chronic pancreatitis (Masson 2013, Steiner 2011, Xiao 2017), or cystic fibrosis (Petrova 2020, Shen 2022). This variant is also reported in ClinVar database (Variation ID: 7238) and is found in the Finnish European population with an allele frequency of 3.5% (875/25118 alleles, including 25 homozygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.546). However, functional analyses of the variant protein show reduced function in vitro (Hammerle 2001, Lee 2003). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Cheng H et al. Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with congenital bilateral absence of vas deferens. J Assist Reprod Genet. 2022 Mar;39(3):719-728. PMID: 35119551. Fang J et al. Congenital absence of the vas deferens with hypospadias or without hypospadias: Phenotypic findings and genetic considerations. Front Genet. 2022 Nov 9;13:1035468. PMID: 36437957. Guan et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. PMID: 29997923. Hammerle MM et al. Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability. J Biol Chem. 2001 May 4;276(18):14848-54. PMID: 11278813. Lee JH et al. A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet. 2003 Sep 15;12(18):2321-32. PMID: 12952861. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 11(4):316-23. PMID: 22483971. Luo et al. Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. Gene. 2021 Jan 10;765:145045. PMID: 32777524. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 8(8):e73522. PMID: 23951356. Petrova NV et al. Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients. Genes (Basel). 2020 May 15;11(5):554. PMID: 32429104. Shen Y et al. Genetic spectrum of Chinese children with cystic fibrosis: comprehensive data analysis from the main referral centre in China. J Med Genet. 2022 Jul 20;60(3):310–5. PMID: 35858753. 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. Xiao et al. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. J Pediatr. 2017 Dec;191:158-163.e3. PMID: 29173301.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000586415	SCV005197451	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000007660	SCV000027861	pathogenic	Cystic fibrosis	2003-09-15	no assertion criteria provided	literature only
Natera, Inc.	RCV000007660	SCV001453952	uncertain significance	Cystic fibrosis	2017-06-13	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000586415	SCV001743728	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586415	SCV001965527	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001095295	SCV002507455	uncertain significance	CFTR-related disorder	2021-04-29	no assertion criteria provided	clinical testing