ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.772A>G (p.Arg258Gly) (rs191456345)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047251 SCV000075264 uncertain significance Cystic fibrosis 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 258 of the CFTR protein (p.Arg258Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs191456345, ExAC 0.2%). This variant has been reported in the literature in individuals affected with congenital absence of the vas deferens, contralateral dysplasia of seminal vesicle, chronic pancreatitis, and bronchiectasis (PMID: 7529962, 19810821, 17413420, 10875853). ClinVar contains an entry for this variant (Variation ID: 54055). Experimental studies have shown that this missense change causes mis-processing of the CFTR protein in vitro (PMID: 9305991, 16196493). In summary, this variant is a rare missense change that has been shown to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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
Integrated Genetics/Laboratory Corporation of America RCV000588144 SCV000697044 likely pathogenic Congenital bilateral absence of the vas deferens 2018-08-07 criteria provided, single submitter clinical testing Variant summary: CFTR c.772A>G (p.Arg258Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 262596 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 (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). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic for CBAVD.
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 Clinical Services Laboratory,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,Partners HealthCare Personalized Medicine RCV000588144 SCV000966827 likely pathogenic Congenital bilateral absence of the vas deferens 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.

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