rs267606723

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.3731G>A(p.Gly1244Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic,drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1244R) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:12O:1

Conservation

PhyloP100: 9.19

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain 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 chr7-117642450-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53796.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 7-117642451-G-A is Pathogenic according to our data. Variant chr7-117642451-G-A is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 53797.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117642451-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3731G>A	p.Gly1244Glu	missense_variant	23/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3731G>A	p.Gly1244Glu	missense_variant	23/27	1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.65+4900C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250996

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461342

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 16, 2015	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2023	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1244 of the CFTR protein (p.Gly1244Glu). This variant is present in population databases (rs267606723, gnomAD 0.002%). This missense change has been observed in individuals with cystic fibrosis and congenital absence of the vas deferens (PMID: 10636451, 10923036, 21520337, 22020151, 23974870). ClinVar contains an entry for this variant (Variation ID: 53797). 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: 11242048, 23974870). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 30, 2021	The p.G1244E pathogenic mutation (also known as c.3731G>A), located in coding exon 23 of the CFTR gene, results from a G to A substitution at nucleotide position 3731. The glycine at codon 1244 is replaced by glutamic acid, an amino acid with similar properties. This mutation was first described in a clinically affected individual with elevated sweat chloride levels and pancreatic insufficiency in conjunction with p.F508del (Devoto M et al. Am. J. Hum. Genet., 1991 Jun;48:1127-32). In another study, this mutation was identified in an individual with elevated sweat chloride levels, pancreatic insufficiency, and gastrointestinal and pulmonary symptoms of classic cystic fibrosis in conjunction with a frameshift alteration on the other chromosome (Kilinç MO et al. J. Med. Genet., 2000 Apr;37:307-9). This mutation was detected as homozygous in an individual with elevated sweat chloride levels and an overall clinical presentation consistent with cystic fibrosis (Petrova NV et al. Clin Genet, 2019 03;95:444-447). This mutation is typically associated with elevated sweat chloride levels, pancreatic insufficiency, and pulmonary symptoms (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). Functional analyses demonstrate that this mutation significantly reduces protein activity (Anderson MP et al. Science, 1992 Sep;257:1701-4; Choi JY et al. Nature, 2001 Mar;410:94-7; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 31, 2016	Variant summary: The CFTR c.3731G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Glu. 5/5 in-silico tools predict a damaging outcome for this variant, and G1244E has been shown to drastically reduce chloride channel activity and HCO3- transport by in vitro studies (Anderson et al 1992, Choi et al 2001, Yu et al 2012, and Sosnay et al 2013). This variant was found in 2/121206 control chromosomes at a frequency of 0.0000165, which does not exceed maximal expected frequency of a pathogenic CFTR allele (0.0129603). In addition, the CFTR2 database and several independent publications consider the variant pathogenic/CF-causing. Taken together, this variant was classified as pathogenic. -

CFTR-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 16, 2024	The CFTR c.3731G>A variant is predicted to result in the amino acid substitution p.Gly1244Glu. This variant has been reported in the homozygous or compound heterozygous state in individuals with cystic fibrosis (see, for example, Devoto et al. 1991. PubMed ID: 1709778; D'Apice et al. 2004. PubMed ID: 15614862; Mesbahi et al. 2016. PubMed ID: 27659740). It has also been detected in individuals with congenital bilateral absence of vas deferens (Supporting Table S5, Steiner et al. 2011. PubMed ID: 21520337). In vitro functional studies suggest this variant impacts protein function (Choi et al. 2001. PubMed ID: 11242048; Sosnay et al. 2013. PubMed ID: 23974870). In addition, alternative nucleotide changes affecting the same amino acid (p.Gly1244Arg, p.Gly1244Val) have also been reported in individuals with cystic fibrosis (Lucarelli et al. 2015. PubMed ID: 25910067; Ziętkiewicz et al. 2014. PubMed ID: 24586523; Savov et al. 1994. PubMed ID: 7516777). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Hereditary pancreatitis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 23, 2024

- -

ivacaftor response - Efficacy

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

5.1

H;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.8

D;D;.

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

1.0

D;.;.

Vest4

1.0

MutPred

0.98

Loss of methylation at R1245 (P = 0.0428);.;.;

MVP

1.0

MPC

0.015

ClinPred

1.0

GERP RS

4.7

Varity_R

0.99

gMVP

0.99

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