7-117531002-G-A

Position:

• chr7-117531002-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic reviewed by expert panel P:15 O:1
• Conservation: PhyloP100: 9.52

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 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	c.377G>A	p.Gly126Asp	missense_variant	4/27	ENST00000003084.11	NP_000483.3

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250898 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135582

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: 6 AN: 1461460 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727038

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.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7 Other: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	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.9	M;.;.;.;M
PrimateAI	Uncertain	0.78	T
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	D
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

Other links and lift over

dbSNP: rs397508609; hg19: chr7-117171056;