ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1001G>A (p.Arg334Gln) (rs397508137)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046192 SCV000074205 uncertain significance Cystic fibrosis 2019-09-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 334 of the CFTR protein (p.Arg334Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs397508137, ExAC 0.02%). This variant has been reported in unaffected individuals as well as in an infertile male with no sign of cystic fibrosis and in an individual affected with congenital bilateral absence of the vas deferens who also had one known pathogenic mutation in CFTR (PMID: 11379874, 16126774, 19897426, 15070876). It has also been reported in an individual with typical or atypical cystic fibrosis (PMID: 28546993). ClinVar contains an entry for this variant (Variation ID: 53159). Experimental studies have shown that this missense change alters anion binding at the CFTR chloride channel pore (PMID: 12679372, 17673962, 25892339, 22612315). However, studies describing the impact of this change on chloride ion conductance are conflicting (PMID: 15130785, 25277268). The clinical significance of these findings are unknown. In addition, a different missense substitution at this codon (p.Arg334Trp) has been determined to be pathogenic (PMID: 15371902, 23974870). This suggests that the arginine residue is critical for CFTR protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare variant that may disrupt protein function or mRNA splicing and has been found in affected individuals. However, it has also been observed in unaffected individuals and segregation studies have not been reported. The available evidence is currently insufficient to determine its role in disease. For these reasons, this change has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000587058 SCV000603057 likely pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing The CFTR c.1001G>A, p.Arg334Gln variant (rs397508137) has been described in the literature in individuals with atypical cystic fibrosis as well as seemingly healthy adults (Dayangac 2004, Picci 2010). However functional studies have shown this variant to cause a disruption of anion interactions with the CFTR pore (Gong 2003, Linsdell 2015, Smith 2001, Zhou 2007), resulting in reduced chloride conductance (Gong 2004). Other missense variants at this residue have also been implicated in affecting CFTR protein functions (Gong 2003, Gong 2004, Smith 2001, Sosnay 2013, Zhou 2007). The p. Arg334Gln variant is listed in ClinVar (Variation ID: 53159), and observed in the general population databases at a frequency of 0.02 percent in the 1000 Genomes Project, and 0.01 percent in the Exome Aggregation Consortium. The arginine at residue 334 is highly conserved, but computational algorithms (Align GVGD: c0; Mutation Taster: disease-causing; PolyPhen-2: probably damaging; SIFT: tolerated) are inconclusive on the variant's impact on the protein. Based on the above information, the variant is classified as likely pathogenic. References: Dayangac D et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2004; 19(5):1094-100. Gong X et al. Molecular determinants and role of an anion binding site in the external mouth of the CFTR chloride channel pore. J Physiol. 2003; 549(Pt 2):387-97. Gong X et al. Maximization of the rate of chloride conduction in the CFTR channel pore by ion-ion interactions. Arch Biochem Biophys. 2004; 426(1):78-82. Linsdell P. Interactions between permeant and blocking anions inside the CFTR chloride channel pore. Biochim Biophys Acta. 2015; 1848(7):1573-90. Picci L et al. A 10-year large-scale cystic fibrosis carrier screening in the Italian population. J Cyst Fibros. 2010; 9(1):29-35. Smith S et al. CFTR: covalent and noncovalent modification suggests a role for fixed charges in anion conduction. J Gen Physiol. 2001; 118(4):407-31. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Zhou J et al. Direct and indirect effects of mutations at the outer mouth of the cystic fibrosis transmembrane conductance regulator chloride channel pore. J Membr Biol. 2007; 216(2-3):129-42.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587058 SCV000696814 uncertain significance not provided 2017-02-08 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1001G>A (p.Arg334Gln) variant involves the alteration of a conserved nucleotide. This variant is located in the ABC transporter type 1, transmembrane domain (InterPro) and R334 may interact with extracellular Cl- (PMID: 24341413). 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 17/121332 control chromosomes at a frequency of 0.0001401, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant has been found in at least two CBAVD patients in heterozygous state, one of whom carries a pathogenic CFTR variant (R347H, Dayangac_2004, Havasi_2010). However, one 38 y/o male patient had R334Q/R553X but no CBAVD or other disease condition (Picci_2010), suggesting this variant is benign or has low penetrance. One functional study showed moderate and non-significant decrease of chloride stimulation of forskolin-activated currents in CFTR R334Q compared to WT CFTR (Broadbent_2015). Another missense at the same codon, R334W, has been classified as pathogenic. Taken together, this variant is classified as a Variant of Uncertain Significance, until additional information becomes available.
Counsyl RCV000046192 SCV000795897 uncertain significance Cystic fibrosis 2017-11-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000587058 SCV000854926 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587058 SCV000888063 uncertain significance not provided 2018-05-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV001009633 SCV001169725 likely pathogenic Inborn genetic diseases 2020-05-15 criteria provided, single submitter clinical testing The p.R334Q variant (also known as c.1001G>A), located in coding exon 8 of the CFTR gene, results from a G to A substitution at nucleotide position 1001. The arginine at codon 334 is replaced by glutamine, an amino acid with highly similar properties. In our own clinical cohort, this variant has been detected in conjunction with a pathogenic mutation presumably in trans in an individual with elevated sweat chloride levels. The R334Q protein also reduces the chloride conductance of CFTR and may lead to the clinical manifestation of cystic fibrosis due to disruption of multi-ion pore behavior and consequent loss of chloride efflux capacity (Gong X et al. Arch. Biochem. Biophys., 2004 Jun;426:78-82; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077; Han ST et al. JCI Insight, 2018 07;3:). In addition, the alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; The Clinical and Functional TRanslation of CFTR (CFTR2); available at Accessed April 17, 2018). There are also two well-characterized pathogenic mutations, p.R334W and p.R334L, located at the same position as this variant (Ooi CY et al. J. Cyst. Fibros., 2012 Sep;11:355-62; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV001165384 SCV001327573 uncertain significance CFTR-related disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000587058 SCV001714227 likely pathogenic not provided 2021-03-09 criteria provided, single submitter clinical testing PS3, PM2, PM5

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