rs201124247

Positions:

• chr7-117592008-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D614N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 8.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain 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/exons	MANE	UniProt
CFTR	NM_000492.4	c.1841A>G	p.Asp614Gly	missense_variant	14/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1841A>G	p.Asp614Gly	missense_variant	14/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152220 Hom.: 0 Cov.: 33

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: 7 AN: 229320 Hom.: 0 AF XY: 0.0000483 AC XY: 6 AN XY: 124222

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: 12 AN: 1440326 Hom.: 0 Cov.: 31 AF XY: 0.00000978 AC XY: 7 AN XY: 715700

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: 2 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74492

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: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 11, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jan 31, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 24, 2023	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. Experimental studies have shown that this missense change affects CFTR function (PMID: 9736778). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 11, 2023	- -

CFTR-related disorder Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jan 31, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 12, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 28, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 03, 2022	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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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Cystic fibrosis;na:CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jul 03, 2015

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 20, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
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	D
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

Other links and lift over

dbSNP: rs201124247; hg19: chr7-117232062;