ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.772A>G (p.Arg258Gly)

gnomAD frequency: 0.00011  dbSNP: rs191456345
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047251 SCV000075264 pathogenic Cystic fibrosis 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 258 of the CFTR protein (p.Arg258Gly). This variant is present in population databases (rs191456345, gnomAD 0.08%). This missense change has been observed in individuals with CFTR-related conditions (PMID: 7529962, 10376575, 11466205, 19810821). ClinVar contains an entry for this variant (Variation ID: 54055). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 9305991, 16196493, 23104983). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga) RCV000723753 SCV000331503 uncertain significance not provided 2017-06-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000349995 SCV000601132 uncertain significance not specified 2017-04-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588144 SCV000697044 likely pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2023-04-13 criteria provided, single submitter clinical testing Variant summary: CFTR c.772A>G (p.Arg258Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPRIPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 236970 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence of the Vas Deferens (CBAVD) (0.00017 vs 0.013), allowing no conclusion about variant significance. This variant has been reported in CBAVD patients in compound heterozygosity with disease causing CFTR alleles including DeltaF508, Ser945Leu, and Tyr1092X, indicating pathogenicity for CBAVD (examples: Chillon_1995, Masvidal_2009). Additionally, a functional study on this mutation revealed that the Arg258Gly variant disrupts biosynthesis of the protein; inhibits maturation and transport of the CFTR protein to the cell surface, and reduces the anion translocation capability of CFTR (Seibert et al., 1997) further supporting a deleterious impact. However, one recent functional study reported the variant to have wild-type levels of CFTR-dependent Cl- transport (Pranke_2017). Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=8) and VUS (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl RCV000047251 SCV000799544 uncertain significance Cystic fibrosis 2018-04-24 criteria provided, single submitter clinical testing
Mendelics RCV000047251 SCV000886145 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000047251 SCV000916178 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter clinical testing The CFTR c.772A>G (p.Arg258Gly) missense variant has been reported in four studies in which it is found in a total of seven affected individuals including in a compound heterozygous state in three individuals affected with congenital bilateral absence of vas deferens (CBAVD) (Mercier et al. 1995; Casals et al. 2000; Masvidal et al. 2009); in a compound heterozygous state in one individual affected with congenital unilateral absence of vas deferens (CUAVD) plus contralateral dysplasia of seminal vesicle (Masvidal et al. 2009); and in a heterozygous state in one individual affected with CBAVD (Grangeia et al. 2007), one individual affected with chronic pancreatitis and another with bronchiectasis (Masvidal et al. 2009). The individual with bronchiectasis also carried a known complex allele in cis (Masvidal et al. 2009). The p.Arg258Gly variant has not been reported in association with cystic fibrosis.The p.Arg258Gly variant was absent from 374 unaffected individuals and 250 cystic fibrosis patients (Mercier et al. 1995; Masvidal et al. 2009) but is reported at a frequency of 0.00167 in the Latino population of the Exome Aggregation Consortium. The variant is located in the second intracellular loop of the CFTR protein, a region known to highly conserved and contain other missense variants resulting in a CFTR-related disorders phenotype. Expression studies in HEK-293 and in CHO cells showed that the p.Arg258Gly variant resulted in incomplete glycosylation (less than 5% of wildtype levels) and was not transported to the cell surface (Seibert et al. 2007). Lack of surface expression resulted in loss of anion translocation capability of the CFTR protein (Seibert et al. 2007). Surface expression of the variant protein could be rescued by incubation of BHK cells stably transfected with the p.Arg258Gly variant with a quinazoline derivative, as determined by the iodide efflux assay (Loo et al. 2005). Based on the collective clinical and functional evidence, the p.Arg258Gly 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000588144 SCV000966827 likely pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-23 criteria provided, single submitter clinical testing The p.Arg258Gly variant in CFTR has been reported in 7 individuals with CFTR-rel ated disorders, including 4 with congenital absence of the vas deferens (CAVD; M ercier 1995, Casals 2000, Grangeia 2007, Masvidal 2009). In three individuals, a variant affecting the second copy of CFTR was not identified. In the other 4 in dividuals, all of whom with CAVD, the p.Arg258Gly was identified in the compound heterozygote state with other CFTR variants, of which at least three were patho genic. The p.Arg258Gly variant has also been reported by other clinical laborato ries in ClinVar (Variation ID: 54055). In vitro functional studies provide some evidence that the p.Arg258Gly variant may impact protein function due to imprope r shuttling to the plasma membrane (Seibert 1997, Loo 2005). Additionally, this variant has been identified in 27/33360 Latino chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consi stent with a recessive carrier frequency. Computational prediction tools and con servation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establis h its clinical significance, the p.Arg258Gly variant is likely pathogenic for CF TR-related disorders, particularly CVAD, in an autosomal recessive manner based upon presence in multiple affected individuals and functional evidence . ACMG/AM P criteria applied: PM3_VeryStrong, PS3_Moderate.
CFTR-France RCV002281738 SCV001169233 pathogenic CFTR-related disorder 2021-01-18 criteria provided, single submitter curation
Ambry Genetics RCV000047251 SCV001189199 likely pathogenic Cystic fibrosis 2023-10-25 criteria provided, single submitter clinical testing The p.R258G variant (also known as c.772A>G), located in coding exon 7 of the CFTR gene, results from an A to G substitution at nucleotide position 772. The arginine at codon 258 is replaced by glycine, an amino acid with dissimilar properties. This alteration was first described in trans with p.F508del in a male with congenital bilateral absence of the vas deferens (CBAVD) (Mercier B et al. Am. J. Hum. Genet., 1995 Jan;56:272-7). Another study described this variant in five unrelated individuals with CFTR-related disorders; three individuals with CBAVD were compound heterozygotes with another CFTR alteration, while one individual with chronic pancreatitis carried only this alteration and one individual with bronchiectasis carried this alteration in cis with two other CFTR alterations (Masvidal L et al. Genet Test Mol Biomarkers, 2009 Dec;13:765-8). This alteration was also identified in a male with CBAVD in conjunction with p.S945L; however, the phase was not provided (Casals T et al. Hum. Reprod., 2000 Jul;15:1476-83). A functional study found this alteration inhibited the maturation and transportation of the CFTR protein to the cell surface (Seibert FS et al. Biochemistry, 1997 Sep;36:11966-74). The p.R258G variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 15, 2020). 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.
CeGaT Center for Human Genetics Tuebingen RCV000723753 SCV001250502 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000723753 SCV001714223 uncertain significance not provided 2020-10-02 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000047251 SCV001822022 likely pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000723753 SCV003799648 pathogenic not provided 2022-10-14 criteria provided, single submitter clinical testing The CFTR c.772A>G; p.Arg258Gly variant (rs191456345) is reported in the literature in multiple individuals affected with congenital absence of the vas deferens or other CFTR-related disorders, including several individuals who carried a second pathogenic CFTR variant (Casals 2000, Chillon 1995, Masvidal 2009, Mercier 1995). This variant is also reported in the CFTR2 database, and in ClinVar (Variation ID: 54055). This variant is found in the general population with an overall allele frequency of 0.017% (46/267144 alleles) in the Genome Aggregation Database. The arginine at codon 258 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.896). Functional analyses of the variant protein show reduced cell surface expression and decreased channel function (Seibert 1997). Based on available information, this variant is considered to be mildly pathogenic, but is not predicted to cause classic cystic fibrosis. References: Link to CFTR2 database: https://cftr2.org/ Casals T et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod. 2000 Jul;15(7):1476-83. PMID: 10875853. Chillon M et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995 Jun 1;332(22):1475-80. PMID: 7739684. Masvidal L et al. The p.Arg258Gly mutation in intracellular loop 2 of CFTR is associated with CFTR-related disorders. Genet Test Mol Biomarkers. 2009 Dec;13(6):765-8. PMID: 19810821. Mercier B et al. Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients. Am J Hum Genet. 1995 Jan;56(1):272-7. PMID: 7529962. Seibert FS et al. Disease-associated mutations in cytoplasmic loops 1 and 2 of cystic fibrosis transmembrane conductance regulator impede processing or opening of the channel. Biochemistry. 1997 Sep 30;36(39):11966-74. PMID: 9305991.
PreventionGenetics, part of Exact Sciences RCV002281738 SCV004119827 likely pathogenic CFTR-related disorder 2022-11-21 criteria provided, single submitter clinical testing The CFTR c.772A>G variant is predicted to result in the amino acid substitution p.Arg258Gly. This variant has been reported in the compound heterozygous state with known pathogenic variants in patients with cystic fibrosis related disorders including congenital bilateral absence of vas deferens, chronic pancreatitis and bronchiectasis (Chillón et al. 1995. PubMed ID: 7739684; Mercier et al. 1995. PubMed ID: 7529962; Mak et al. 1999. PubMed ID: 10376575; Larriba et al. 2001. PubMed ID: 11466205; Masividal et al. 2009. PubMed ID: 19810821). Expression studies in COS-1 and HEK293 cells showed impaired CFTR surface expression (Seibert et al. 1997. PubMed ID: 9305991). This variant is reported in 0.090% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117176630-A-G). This variant is interpreted as likely pathogenic.
Baylor Genetics RCV003474618 SCV004213377 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-09-19 criteria provided, single submitter clinical testing

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