rs397508137
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM2PM5PP5BP4
The NM_000492.4(CFTR):c.1001G>A(p.Arg334Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334L) has been classified as Pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.1001G>A | p.Arg334Gln | missense_variant | Exon 8 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000921 AC: 14AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251222Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135766
GnomAD4 exome AF: 0.000194 AC: 284AN: 1461848Hom.: 0 Cov.: 31 AF XY: 0.000198 AC XY: 144AN XY: 727220
GnomAD4 genome 0.0000920 AC: 14AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74390
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:5Uncertain:3
VarIant NM_000492.4(CFTR):c.1001G>A (p.Arg334Gln) has GnomAD 4.1 frequency of 0.0001846 with 0 homozygote. Reported as likely pathogenic in PMID 29805046 -
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This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 334 of the CFTR protein (p.Arg334Gln). This variant is present in population databases (rs397508137, gnomAD 0.09%). This missense change has been observed in individual(s) with typical or atypical cystic fibrosis. Also, it has been identified in unaffected individuals as well as an individual affected with congenital bilateral absence of the vas deferens who also had one known pathogenic mutation in CFTR (PMID: 11379874, 15070876, 16126774, 19897426, 28546993). ClinVar contains an entry for this variant (Variation ID: 53159). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 12679372, 15130785, 17673962, 22612315, 25277268, 25892339). This variant disrupts the p.Arg334 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15371902, 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Variant summary: CFTR c.1001G>A (p.Arg334Gln) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 251222 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00011 vs 0.013), allowing no conclusion about variant significance. c.1001G>A has been reported in the literature in the compound heterozygous state together with a pathogenic variant (p.Trp1282X, F508del) in multiple individuals affected with Cystic Fibrosis, although often these individuals have atypical CF with intermmediate sweat chloride levels and/or a mild phenotype (e.g. Behar_2017, Munck_2020, McCague_2019). It has also been found in at least two individuals with CBAVD, one of whom was compound heterozygous together with a pathogenic CFTR variant (p.Arg347His) (e.g. Dayangac_2004, Havasi_2010). However, the variant has also been reported together with a pathogenic variant (p.Arg553X) in a 38 year old male patient without CF, CBAVD, or other CFTR-related conditions (Picci_2010), suggesting it may have low penetrance. Several publications report experimental evidence evaluating an impact on protein function (e.g. Smith_2001, Broadbent_2015, Wang_2016, Han_2018, Raraigh_2018). At least two studies showed this variant results in approximately 20-30% chloride channel function compared to the WT protein (Han_2018, Raraigh_2018, Bihler_2024). Additionally, other missense variants at the same codon, R334W and R334L, have been classified as pathogenic suggesting the arginine residue is important for CFTR protein function. Having been observed in individuals with CF/ atypical CF, CFTR-related disorders, and healthy individuals, and due to its level of activity versus the WT, this variant has been described as having variable clinical consequences (e.g. Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 28546993, 21228398, 33572515, 25277268, 22439019, 15070876, 26493493, 30046002, 20100616, 17440499, 11379874, 25892339, 34405919, 16126774, 31916691, 19897426, 34782259, 11585852, 27175795, 30888834, 29805046, 38388235). ClinVar contains an entry for this variant (Variation ID: 53159). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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. This variant has been detected in conjunction with a pathogenic mutation in multiple individuals with intermediate sweat chloride levels and/or CFTR-related disorders, as well as seeming healthy adults (Dayangaç D et al. Hum Reprod, 2004 May;19:1094-100; Picci L et al. J Cyst Fibros, 2010 Jan;9:29-35; Behar DM et al. Mol Genet Genomic Med, 2017 May;5:223-236; Munck A et al. Pediatr Pulmonol, 2020 04;55:918-928; Ambry internal data). Although this variant did not completely abolish CFTR function, it impaired CFTR function significantly (Gong X et al. Arch. Biochem. Biophys., 2004 Jun;426:78-82; Linsdell P. Biochim Biophys Acta, 2015 Jul;1848:1573-90; Han ST et al. JCI Insight, 2018 07;3: Raraigh KS et al. Am J Hum Genet, 2018 06;102:1062-1077). 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 http://cftr2.org. Accessed August 23, 2022). 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 available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, it likely contributes to the development of a CFTR-related disorder. This alteration is thus classified as likely pathogenic. -
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not provided Pathogenic:3Uncertain:2
The CFTR c.1001G>A (p.Arg334Gln) variant has been reported in the published literature in individuals with congenital bilateral absence of the vas deferens (PMID: 15070876 (2004), 16126774 (2005), and 20100616 (2010)) and Cystic Fibrosis (PMID: 28546993 (2017), 31916691 (2020)). This variant was also found in unaffected individuals, one of whom also carried a pathogenic CFTR variant (PMID: 11379874 (2001) and 19897426 (2010)). Functional studies have shown this variant disrupts anion binding at the CFTR channel pore, but with inconclusive effects on chloride-stimulated conductance (PMID: 12679372 (2003), 17673962 (2007), 25892339 (2015), and 25277268 (2015)). This variant was found to have a modest response to CFTR modulators (PMID: 30046002 (2018)). The frequency of this variant in the general population, 0.0022 (6/2668 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23974870, 11379874, 15070876, 11427889, 30046002, 25892339, 9922375, 20100616, 16126774, 35451201, 34782259, 32357917, 21228398, 17673962, 15371902, 25277268, 11585852, 15130785, 22612315, 27175795, 29805046, 12679372, 30146269, 34426522, 32773111, 34405919, 36207272, 33444622, 19897426, 11180668, 17440499, 28546993, 32784480, 33572515, 31916691, 36969284, 36670555, 34888852, 38515211, 34996830, 36428953, 37628659, 36910284, 27086061, 19669005, 30134826, 38388235, 37823914, 37888495, 39841779, 39262237) -
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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. -
CFTR-related disorder Pathogenic:2Uncertain:1
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. -
The CFTR c.1001G>A variant is predicted to result in the amino acid substitution p.Arg334Gln. This variant has been shown to weaken CFTR channel function and has been reported in patients with congenital bilateral absence of vas deferens (Li et al. 2012. PubMed ID: 22612315; Dayangac et al. PubMed ID: 15070876; Morea et al. 2005. PubMed ID: 16126774). This variant is reported in 0.096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Another missense change at the same amino acid position (p.Arg334Trp) has previously been reported to be causative for cystic fibrosis (see supplemental table 2 in Sosnay et al. 2013. PubMed ID: 23974870). This variant is interpreted as likely pathogenic. -
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Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
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Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
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Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at