rs201124247

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):c.1841A>G(p.Asp614Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000879 in 1,592,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 8.60

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

PP5

Variant 7-117592008-A-G is Pathogenic according to our data. Variant chr7-117592008-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117592008-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.1841A>G	p.Asp614Gly	missense_variant	Exon 14 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.1841A>G	p.Asp614Gly	missense_variant	Exon 14 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000305

AC:

AN:

229320

Hom.:

AF XY:

0.0000483

AC XY:

AN XY:

124222

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.000139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000833

AC:

AN:

1440326

Hom.:

Cov.:

AF XY:

0.00000978

AC XY:

AN XY:

715700

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000130

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000542

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:6Other:1

Mar 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 614 of the CFTR protein (p.Asp614Gly). This variant is present in population databases (rs201124247, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital absence of vas deferens and/or cystic fibrosis (PMID: 12454843, 16478680, 17413420, 21679131). ClinVar contains an entry for this variant (Variation ID: 53403). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 9736778). For these reasons, this variant has been classified as Pathogenic. -

Jan 31, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1841A>G (p.Asp614Gly) results in a non-conservative amino acid change located in the ABC transporter-like (IPR003439) and AAA+ ATPase domains (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 229320 control chromosomes. c.1841A>G has been reported in compound heterozygosity with another pathogenic variant in multiple individuals affected with CF and CBAVD in the literature (e.g. Wilschanski_1995, Grangeia_2004, Lucarelli_2015, Pereira_2019, McCague_2019). Many of these patients have been reported with borderline sweat chloride levels and/or as pancreatic-sufficient, suggesting that the variant may be associated with a milder non-classical CF phenotype. The variant was also detected in compound heterozygosity with the common severe disease causing variant CFTR p.Phe508del in three siblings diagnosed in adulthood with atypical CF phenotypes of varying degrees of severity, leading the authors to conclude that this variant may be a "mild" CF mutation (e.g. Castaldo_2006). Collectively, these data indicate that the variant is likely to be associated with disease. Several publications report in-vitro experimental evidence evaluating an impact on protein function, reporting that the variant reduced CFTR processing in multiple cell lines (e.g. Pasyk_1998 Vankeerberghen_1998, Sosnay_2013). The variant was also observed to at least partially reduce measured current activity and alter the dynamics of channel gate opening and closing (Pasyk_1998, Sosnay_2013). Four clinical diagnostic laboratories and the CFTR-France database have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as Pathogenic/Likely pathogenic (n=4). The CFTR2 database reports the variant as having varying consequences as some individuals with this variant and another pathogenic variant have CF, while others do not, indicating that clinical criteria alone should be used in the diagnosis of patients with this variant. Based on the evidence outlined above, the variant was classified as pathogenic for non-classic CF. -

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 11, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D614G pathogenic mutation (also known as c.1841A>G), located in coding exon 14 of the CFTR gene, results from an A to G substitution at nucleotide position 1841. The aspartic acid at codon 614 is replaced by glycine, an amino acid with similar properties. This mutation has been detected in three individuals from one family with mild CF who also carried the p.F508del pathogenic mutation in trans (Castaldo G et al. J. Cyst. Fibros., 2006 Aug;5:193-5). This alteration has also been detected in individuals with CFTR-related disorders, including CBAVD and pancreatitis (Zielenski J et al. Am. J. Hum. Genet., 1995 Oct;57:958-60; Gomez-Lira M et al. Eur. J. Hum. Genet., 2003 Jul;11:543-6; Amato F et al. J Mol Diagn, 2012 Jan;14:81-9). The p.D614G alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am. 2016 Aug;63(4):585-98). In addition, in vitro functional studies have demonstrated this alteration results in decreased chlorine channel activity and abnormal protein processing (Pasyk EA et al. J. Biol. Chem., 1998 Nov;273:31759-64; Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). 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 the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Mar 11, 2023

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder

Pathogenic:3

Jan 31, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 12, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1841A>G variant is predicted to result in the amino acid substitution p.Asp614Gly. This variant has been reported in individuals with an indeterminate cystic fibrosis phenotype (Supplementary Table 2, Sosnay et al. 2013. PubMed ID: 23974870; Masica et al. 2014. PubMed ID: 25489051) and in an individual with congenital bilateral absence of the vas deferens (CBAVD, Amato et al. 2011. PubMed ID: 22020151). This variant was also reported in the compound heterozygous state with the F508del variant in three siblings with late-diagnosed mild cystic fibrosis, however one sibling had severe symptoms while the other two had a milder disease course (Castaldo et al. 2006. PubMed ID: 16478680). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117232062-A-G). Taken together, this variant is interpreted as likely pathogenic. -

Aug 28, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Jul 11, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect: abnormal protein maturation and misprocessing, decreased cAMP-activated currents, and defective channel opening (PMID: 29040544, 9822639, 9736778); Observed with a pathogenic CFTR variant in multiple individuals with CFTR-related disorders in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 34065744, 16478680, 21679131); Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 9822639, 34065744, 16478680, 21679131, 29040544, 9736778, 25489051, 22020151, 11462247, 8406518, 32185651, 23430892, 23974870) -

Oct 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1841A>G; p.Asp614Gly variant (rs201124247) is reported in the literature in the compound heterozygous state with another pathogenic CFTR variant individuals with phenotypes ranging from cystic fibrosis with or without pancreatic insufficiency to congenital absence of the vas deferens only (Castaldo 2006, Durno 2002, Grangeia 2007, Lucarelli 2015, McCague 2019, Pereira 2019, Tomaiuolo 2011, Wilschanski 1995). This variant is also reported in ClinVar (Variation ID: 53403), but is only observed on seven alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartate at codon 614 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.942). In vitro functional analyses demonstrate aberrant protein processing leading to partial channel function (Pasyk 1998, Sosnay 2013, Vankeerberghen 1998). Based on available information and the range of phenotypes observed, this variant is considered to be pathogenic with varying clinical consequences. References: Castaldo G et al. Phenotypic discordance in three siblings affected by atypical cystic fibrosis with the F508del/D614G genotype. J Cyst Fibros. 2006 Aug;5(3):193-5. PMID: 16478680. Durno C et al. Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology. 2002 Dec;123(6):1857-64. PMID: 12454843. Grangeia A et al. Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens. Genet Med. 2007 Mar;9(3):163-72. PMID: 17413420. Lucarelli M et al. A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis. Mol Med. 2015 Apr 21;21(1):257-75. PMID: 25910067. McCague AF et al. Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis. Am J Respir Crit Care Med. 2019 May 1;199(9):1116-1126. PMID: 30888834. Pasyk EA et al. A conserved region of the R domain of cystic fibrosis transmembrane conductance regulator is important in processing and function. J Biol Chem. 1998 Nov 27;273(48):31759-64. PMID: 9822639. Pereira SV et al. Novel, rare and common pathogenic variants in the CFTR gene screened by high-throughput sequencing technology and predicted by in silico tools. Sci Rep. 2019 Apr 17;9(1):6234. PMID: 30996306. 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. PMID: 23974870. Tomaiuolo R et al. Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment. Clin Chem Lab Med. 2011 Aug;49(8):1289-1293. PMID: 21679131. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 Oct;7(11):1761-9. PMID: 9736778. Wilschanski M et al. Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations. J Pediatr. 1995 Nov;127(5):705-10. PMID: 7472820. -

Oct 03, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.00014 (4/28740 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in patients with classical or atypical cystic fibrosis (CF) (PMIDs: 33424627 (2020), 30996306 (2019), 25910067 (2015), 16801189 (2006), 16478680 (2006), 12454843 (2002)), congenital bilateral absence of vas deferens (CBAVD) (PMIDs: 25910067 (2015), 15333598 (2004)), pancreatic insufficiency (PMIDs: 30888834 (2019), 16478680 (2006)), and is often reported in trans with another pathogenic CFTR variant in affected individuals. Functional studies have indicated that this variant causes abnormal protein folding, abnormal rates of cell maturation, and altered rates of channel opening (PMIDs: 9736778 (1998), 9822639 (1998), 29040544 (2017), 30297908 (2018), 33468668 (2021), 35418593 (2022)). 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, this variant is classified as pathogenic. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Feb 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Jul 03, 2015

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;D;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.3

M;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.6

D;.;D;.

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0080

D;.;D;.

Sift4G

Uncertain

0.013

D;.;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.98

MVP

1.0

MPC

0.0048

ClinPred

0.89

GERP RS

5.5

Varity_R

0.88

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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