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

gnomAD frequency: 0.00039  dbSNP: rs121908759

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	2021-05-03	criteria provided, single submitter	clinical testing	This variant is associated with a variable phenotype and individuals with this variant and a CFTR pathogenic variant associated with classic CF may be affected by a CFTR-related disorder, such as oligospermia, CBAVD, or pancreatic-sufficient CF (PMIDs: 17329263 (2007), 23951356 (2013), 25443471 (2015)). Several functional studies have reported that this variant affects proper CFTR function (PMID 20435887 (2010), 18230692 (2008), 9736778 (1998), 30046002 (2018)). Based on the available information, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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 roadinstitute.org; 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 Laboratory Services, 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 www.CFTR2.org for phenotype information.
CFTR-France	RCV001009381	SCV001169234	pathogenic	Cystic fibrosis; CFTR-related disorder	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	RCV000046498	SCV001174031	likely pathogenic	Cystic fibrosis	2024-05-24	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 http://cftr2.org. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046498	SCV001719369	benign	Cystic fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000506455	SCV001747524	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001588828	SCV001822091	likely pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000506455	SCV001982355	likely pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); Published functional studies are conflicting: normal or reduced protein maturation, reduced chloride transport activity, and reduced protein function (Vankeerberghen 1998, Norez 2008, Billet 2010, Han 2018, Raraigh 2018); Observed in the heterozygous state in an individual with asthma and borderline sweat chloride levels, an individual with oligospermia, an individual with congenital absence of vas deferens, and also in multiple healthy individuals (Vankeerberghen 1998, Monaghan 2004, Luo 2021); Observed in individuals with pancreatitis referred for genetic testing at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29174009, 34996830, 18230692, 9736778, 20435887, 19833837, 22975760, 25489051, 23951356, 15354332, 29805046, 30046002, 30609409, 30032850, 17329263, 25443471, 28603918, 16596947, 31589614, 32777524, 35313924, 34804071, 35314707)
Revvity Omics, Revvity	RCV000506455	SCV002019249	pathogenic	not provided	2022-10-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506455	SCV002047967	pathogenic	not provided	2021-04-02	criteria provided, single submitter	clinical testing	The CFTR c.1865G>A; p.Gly622Asp variant (rs121908759) is reported in the compound heterozygous state in multiple individuals with symptoms ranging from classic cystic fibrosis to CFTR-related disorders, such as male infertility and pancreatitis (Ceyhan-Birsoy 2019, Masson 2013, Marion 2015, Ratbi 2007, Vankeerberghen 1998). This variant is also reported in ClinVar (Variation ID: 35833), and is observed in the general population with an overall allele frequency of 0.012% (34/274254 alleles) in the Genome Aggregation Database. The glycine at residue 622 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.964). Functional characterization of the variant protein indicates a defect in CFTR processing and maturation, leading to a reduced chloride transport activity (Billet 2010, Raraigh 2018, Vankeerberghen 1998). Based on the above information, the variant is classified as pathogenic with varying clinical consequences. References: Billet A et al. C terminus of nucleotide binding domain 1 contains critical features for cystic fibrosis transmembrane conductance regulator trafficking and activation. J Biol Chem. 2010 285(29):22132-40. Ceyhan-Birsoy O et al. Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. Am J Hum Genet. 2019 Jan 3;104(1):76-93. Marion H et al. The p.Gly622Asp (G622D) mutation, frequently found in Reunion Island and in black populations, is associated with a wide spectrum of CF and CFTR-RD phenotypes. J Cyst Fibros. 2015 14(3):305-9. 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. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 22(5):1285-91. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 7(11):1761-9.
AiLife Diagnostics, AiLife Diagnostics	RCV000506455	SCV002501205	pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000046498	SCV002503746	pathogenic	Cystic fibrosis	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace glycine with aspartic acid at codon 622 of the CFTR protein, p.(Gly622Asp). The glycine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the ABC transporter 1 domain. There is a moderate physicochemical difference between glycine and aspartic acid. The variant is present in a large population cohort at a frequency of 0.01%, which is consistent with a recessive disorder (rs121908759, 34/274,254 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified compound heterozygous with a second pathogenic allele in multiple cases diagnosed with cystic fibrosis and other CFTR-related disorders (PMID: 25443471). Moderately reduced protein function has been shown with stable expression of the variant in a human airway cell line, and significantly lower intrinsic chloride channel activities in in vitro assays in COS1 cells (PMID: 9736778, 29805046). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PS3_Supporting, PP3.
Sema4, Sema4	RCV002256004	SCV002529684	likely pathogenic	Hereditary pancreatitis	2021-04-12	criteria provided, single submitter	curation
Baylor Genetics	RCV003473129	SCV004211624	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-30	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
Genome-Nilou Lab	RCV000046498	SCV001822090	uncertain significance	Cystic fibrosis	2021-07-22	flagged submission	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002228058	SCV002507475	likely pathogenic	CFTR-related disorder	2021-12-25	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV002228058	SCV004719395	pathogenic	CFTR-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The CFTR c.1865G>A variant is predicted to result in the amino acid substitution p.Gly622Asp. This variant has been reported to be pathogenic for cystic fibrosis and CFTR-related disease (see for example Vankeerberghen et al. 1998. PubMed ID: 9736778; Marion et al. 2015. PubMed ID: 25443471; http://www.genet.sickkids.on.ca/). Experimental studies indicate this variant impacts protein function (Norez et al. 2008. PubMed ID: 18230692). This variant is reported in 0.085% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.