rs397508137

Positions:

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

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:6

Conservation

PhyloP100: 7.60

Variant links:

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a helix (size 18) in uniprot entity CFTR_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117540231-G-T is described in Lovd as [Pathogenic].

PP5

Variant 7-117540231-G-A is Pathogenic according to our data. Variant chr7-117540231-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53159.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Uncertain_significance=6, Pathogenic=2}. Variant chr7-117540231-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.31236058). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1001G>A	p.Arg334Gln	missense_variant	8/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1001G>A	p.Arg334Gln	missense_variant	8/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251222

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000194

AC:

284

AN:

1461848

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

144

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000203

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:4Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2023	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 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 (gnomAD). 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). 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). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Seven submitters classified the variant as pathogenic/likely pathogenic and six classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 29, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Apr 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 25, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not provided

Pathogenic:3Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 13, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 17, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 13, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2024	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) -

CFTR-related disorder

Pathogenic:2Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 30, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Apr 08, 2020	- -

Cystic fibrosis;na:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jul 01, 2022

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

T;.;.;T;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.31

T;T;T;T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

1.1

L;.;.;.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.33

N;.;.;N;.

REVEL

Pathogenic

0.69

Sift

Benign

0.18

T;.;.;T;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.60

MVP

0.99

MPC

0.0039

ClinPred

0.23

GERP RS

4.5

Varity_R

0.25

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over