ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3205G>A (p.Gly1069Arg) (rs200321110)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506564 SCV000603016 pathogenic not provided 2017-08-18 criteria provided, single submitter clinical testing The CFTR c.3205G>A, p.Gly1069Arg variant (rs200321110) has been reported in multiple patients diagnosed with CFTR-related disorders (Ratbi 2007, Masson 2013). It has also been reported in patients with cystic fibrosis (Savov 1994, Angelicheva 1997, Sosnay 2013), but was found in-cis with a truncating variant (Savov 1994). The variant is reported in ClinVar (Variation ID: 53684), and observed in the general population databases at a frequency of 0.04 percent (2/5008 alleles) in the 1000 Genomes Project, 0.05 percent (7/13006 alleles) in the Exome Variant Server, and 0.03 percent (72/276626 alleles) in the Genome Aggregation Database. The glycine at residue 1069 is moderately conserved, and computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2, SIFT) are inconclusive on the variant's impact on the protein. However, based on the observed clinical symptoms of patients with this variant, we consider the p.Gly1069Arg variant as mildly pathogenic. REFERENCES Angelicheva D et al. Cystic fibrosis mutations and associated haplotypes in Bulgaria - a comparative population genetic study. Hum Genet. 1997 Apr;99(4):513-20. 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 Aug 8;8(8):e73522. 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 May;22(5):1285-91. Savov A et al. Identification of six novel mutations in the CFTR gene of patients from Bulgaria by screening the twenty seven exons and exon/intron boundaries using DGGE and direct DNA sequencing. Hum Mol Genet. 1994 Jan;3(1):57-60. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7.
Counsyl RCV000046823 SCV000795750 uncertain significance Cystic fibrosis 2017-11-22 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000506564 SCV000331451 uncertain significance not provided 2016-04-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000046823 SCV000696958 likely pathogenic Cystic fibrosis 2016-12-01 criteria provided, single submitter clinical testing Variant summary: The CFTR c.3205G>A (p.Gly1069Arg) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 28/120340 control chromosomes at a frequency of 0.0002327, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0062697). Compound heterozygotes of this variant and a CF pathogenic variant were found in at least 4 patients with chronic pancreatitis and in 2 patients with pancreatic insufficient CF. One of the reported CP patients with the variant of interest also carried a likely deleterious variant in SPINK1 (N34S) (Masson_PloS One_2013). Additionally, a CF patient reportedly carried the G1069R variant in cis with a truncating variant L88X, this patient was homozygote for both of the variants (Savov_HMG_1995). These co-occurrences with likely pathogenic variants argue against the pathogenicity of the variant of interest. However, in vitro/vivo functional study indicated that the protein with this variant is retained in ER and has lower open probability and a significant reduction in mean burst duration (Seibert_JBC_1996). Another functional study showed protein with this variant failed to prevent a F508 effect on interburst interval (Dong_PNAS_2012), indicating G1069R probably affects the normal function of CFTR protein. CFTR2 lists variant in 10 CF patients with a classification of mutation with varying consequences. Take all together, the variant shows evidences for pathogenicity however more information is necessary to classify it as true pathogenic, therefore it is classified as likely pathogenic.
Invitae RCV000046823 SCV000074836 uncertain significance Cystic fibrosis 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1069 of the CFTR protein (p.Gly1069Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs200321110, ExAC 0.08%). This variant has been reported in individuals with cystic fibrosis or congenital bilateral absence of the vas deferens, but either a second variant in CFTR was not discovered in these individuals (PMID: 23974870, 17329263, 9239681, 25910067) or an alternative cause of disease was found (PMID: 8528204). It has also been reported in individuals with chronic pancreatitis (PMID: 23951356, 25033378, 17003641, 11729110, 25869325, 20460946). ClinVar contains an entry for this variant (Variation ID: 53684). Experimental studies have shown that this missense change does not alter CFTR protein expression or maturation, but does have a mild effect on channel kinetics in cell culture, possibly due to the disruption of an intramolecular protein interaction (PMID: 8662892, 18305154). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506564 SCV000601092 likely pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing

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