ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1865G>A (p.Gly622Asp) (rs121908759)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000506455 SCV000331140 pathogenic not provided 2018-05-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506455 SCV000601063 pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000046498 SCV000711290 likely pathogenic Cystic fibrosis 2015-12-07 criteria provided, single submitter clinical testing The p.Gly622Asp variant in CFTR has been reported in 8 compound heterozygous ind ividuals with CFTR-related disorders who had a pathogenic variant on the second allele (Marion 2014). Four of these individuals had classic cystic fibrosis, whe reas the other four had azoospermia or oligospermia only. In vitro functional st udies provide some evidence that the p.Gly622Asp variant may impact protein func tion (Norez 2008, Billet 2010), although these types of assays may not accuratel y represent biological function. This variant has also been identified in 9/9888 of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b; dbSNP rs121908759). While this variant has been identified in the general population, its frequency is consistent with a recessive carrier fr equency. Computational prediction tools and conservation analysis also suggest t hat the p.Gly622Asp variant may impact the protein, though this information is n ot predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly622 Asp variant is likely pathogenic for CFTR-related disorders with the phenotypic spectrum ranging from male infertility to classic cystic fibrosis.
Fulgent Genetics,Fulgent Genetics RCV000763577 SCV000894416 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000046498 SCV000915206 pathogenic Cystic fibrosis 2017-04-28 criteria provided, single submitter clinical testing The CFTR c.1865G>A (p.Gly622Asp) missense variant was reported in a total of 22 patients including 11 in a compound heterozygous state (five of whom carried one of two well-established pathogenic variants p.Phe508del or p.Tyr122Ter as the second variant), and ten in a heterozygous state with clinical presentations including classic cystic fibrosis (CF) with and without pancreatic sufficiency, male infertility, and fetal echogenic bowel and one in a heterozygous state with oligospermia (Vankeerberghen et al. 1998; Marion et al. 2015). Additionally, the p.Gly622Asp variant is found in a compound heterozygous state in a patient who at four years old was reportedly without any clinical signs of CF but who could manifest symptoms at a later age (Oca et al. 2009). The p.Gly622Asp variant was absent from 400 controls but was identified in three of 412 healthy individuals in a heterozygous state (Masson et al. 2013). The variant is reported at a frequency of 0.00091 in the African population of the Exome Aggregation Consortium database. Functional studies in COS1, COS7 and HEK 293 cells demonstrated that the p.Gly622Asp variant resulted in abnormal intracellular trafficking and reduced CFTR activity (Vankeerberghen et al. 1998; Norez et al. 2008; Billet et al. 2010). Based on the collective evidence, the p.Gly622Asp variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics RCV001004277 SCV001163153 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000046498 SCV001167305 likely pathogenic Cystic fibrosis 2019-11-22 criteria provided, single submitter clinical testing CFTR variant associated with variable clinical consequences. See for phenotype information.
CFTR-France RCV001009381 SCV001169234 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Ambry Genetics RCV001013447 SCV001174031 likely pathogenic Inborn genetic diseases 2020-04-02 criteria provided, single submitter clinical testing The p.G622D variant (also known as c.1865G>A), located in coding exon 14 of the CFTR gene, results from a G to A substitution at nucleotide position 1865. The glycine at codon 622 is replaced by aspartic acid, an amino acid with similar properties. This variant was identified in a child with cystic fibrosis (CF) in conjunction with p.Y122*, but was also identified in an asymptomatic 4 year old in conjunction with p.F508del; however, phase was not provided for either child (Munck A et al. J. Pediatr., 2009 Dec;155:928-930.e1; Oca F et al. Clin. Chem., 2009 Dec;55:2214-7). In a cohort of individuals with classic CF, this variant was identified in four pancreatic insufficient individuals with elevated sweat chloride levels and pulmonary infections in conjunction with a severe CF mutation; however, the phase was not confirmed. In the same study, this variant was seen in eight infertile males in conjunction with a second CFTR alteration (Marion H et al. J. Cyst. Fibros., 2015 May;14:305-9). Functional studies have demonstrated that this alteration results in lower intrinsic chloride channel activities, altered protein trafficking, reduced levels of fully mature CFTR protein, and reduced chloride conductance compared to wild type (Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9; Norez C et al. J. Pharmacol. Exp. Ther., 2008 Apr;325:89-99; Billet A et al. J. Biol. Chem., 2010 Jul;285:22132-40; Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077; Han ST et al. JCI Insight, 2018 Jul;3:). However, this variant retains almost 20% of normal CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077), and as a result, it is considered variant of varying clinical consequence by The Clinical and Functional TRanslation of CFTR (CFTR2) (available at Accessed <September 20, 2019>). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000046498 SCV001719369 benign Cystic fibrosis 2020-12-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000506455 SCV001747524 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000046498 SCV001822090 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV001588828 SCV001822091 likely pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2021-07-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000046498 SCV000052139 pathogenic Cystic fibrosis 2015-04-03 no assertion criteria provided clinical testing

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