rs397508609

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.377G>A(p.Gly126Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,460 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 Pathogenic (★★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15O:1

Conservation

PhyloP100: 9.52

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 16 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 7-117531002-G-A is Pathogenic according to our data. Variant chr7-117531002-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53812.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117531002-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.377G>A	p.Gly126Asp	missense_variant	4/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.377G>A	p.Gly126Asp	missense_variant	4/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250898

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135582

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461460

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:7Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3_STR, PM5, PP3, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 16, 2021	The p.G126D variant (also known as c.377G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 377. The glycine at codon 126 is replaced by aspartic acid, an amino acid with similar properties. This variant was originally reported in an individual with cystic fibrosis who had p.F508del on the other chromosome (Wagner K et al. Hum. Hered.;44:56-7). p.G126D was also detected in another patient with a different pathogenic mutation (Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75). Furthermore, average sweat chloride in patients with this variant is 90 mEq/L, and it has significantly low chloride conductance in CFBE cell lines (The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed <May 20, 2019>). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.001% (3/250898). 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 majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 126 of the CFTR protein (p.Gly126Asp). This variant is present in population databases (rs397508609, gnomAD 0.003%). This missense change has been observed in individuals with clinical feature of CFTR-related conditions (PMID: 8163293, 10439967, 23974870, 25042876, 27214204). ClinVar contains an entry for this variant (Variation ID: 53812). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Feb 11, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 15, 2023	Variant summary: CFTR c.377G>A (p.Gly126Asp) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 1.2e-05 in 250898 control chromosomes. c.377G>A has been reported in the literature as presumed compound heterozygous genotypes in individuals affected with mild features of Cystic Fibrosis and/or Pseudo Bartters syndrome as well as in cohorts from the Canadian CFTR registry (example, Wagner_1994, Desai_2018, Terzik_2019, Palladino_2020), in addition to settings of newborn screening (example, Lucarelli_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11504857, 29944384, 28736296, 33195651, 31523618, 8163293). Multiple clinical diagnostic laboratories and an expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=2 including the expert panel)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 11, 2019	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CFTR: PM3:Very Strong, PM2, PM5, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	The CFTR c.377G>A; p.Gly126Asp variant (rs397508609) is reported in the literature in several compound heterozygous individuals affected with cystic fibrosis (see link to CF database, Desai 2018, Liechti-Gallati 1999, Lucarelli 2015, Palladino 2020, Salinas 2016, Terzic 2019, Wagner 1994). This variant is reported in ClinVar (Variation ID: 53812). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.881). Based on available information, this variant is considered to be likely pathogenic. References: Link to CFTR2 database: http://cftr2.org/ Desai S et al. Clinical Characteristics and Predictors of Reduced Survival for Adult-diagnosed Cystic Fibrosis. Analysis of the Canadian CF Registry. Ann Am Thorac Soc. 2018 Oct;15(10):1177-1185. PMID: 29944384. Liechti-Gallati S et al. Two buffer PAGE system-based SSCP/HD analysis: a general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease. Eur J Hum Genet. 1999 Jul;7(5):590-8. PMID: 10439967. 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. Palladino F et al. Dehydrated patient without clinically evident cause: A case report. World J Clin Cases. 2020 Oct 26;8(20):4838-4843. PMID: 33195651. Salinas DB et al. Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. PLoS One. 2016 May 23;11(5):e0155624. PMID: 27214204. Terzic M et al. Cystic Fibrosis Mutation Spectrum in North Macedonia: A Step Toward Personalized Therapy. Balkan J Med Genet. 2019 Aug 28;22(1):35-40. PMID: 31523618. Wagner K et al. A new missense mutation G126D in exon 4 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Hered. 1994 Jan-Feb;44(1):56-7. PMID: 8163293. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2024	Observed multiple times with a pathogenic variant in unrelated individuals with cystic fibrosis or CBAVD in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (PMID: 28603918, 33195651, 27214204); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23974870, 15463907, 11504857, 8163293, 28603918, 33195651, 28736296, 31523618, 29944384, 10439967, 34405919, 25910067, 27214204, 25042876) -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

CFTR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 11, 2020

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2024

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 25, 2024

- -

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Mar 26, 2020

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;D;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.9

M;.;.;.;M

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.1

D;.;.;D;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.97

MutPred

0.95

Loss of catalytic residue at I125 (P = 0.2465);Loss of catalytic residue at I125 (P = 0.2465);Loss of catalytic residue at I125 (P = 0.2465);Loss of catalytic residue at I125 (P = 0.2465);Loss of catalytic residue at I125 (P = 0.2465);

MVP

1.0

MPC

0.013

ClinPred

0.97

GERP RS

5.7

Varity_R

0.99

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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