rs75961395

chr7-117509123-G-Achr7-117509123-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):c.254G>A(p.Gly85Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000634 in 1,593,676 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 (★★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G85R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic practice guideline P:22 O:1
• Conservation: PhyloP100: 7.71

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 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 chr7-117509123-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 53510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 7-117509123-G-A is Pathogenic according to our data. Variant chr7-117509123-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7143.Status of the report is practice_guideline, 4 stars. Variant chr7-117509123-G-A is described in Lovd as [Pathogenic]. Variant chr7-117509123-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.254G>A	p.Gly85Glu	missense_variant	3/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.254G>A	p.Gly85Glu	missense_variant	3/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152118 Hom.: 0 Cov.: 33

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250880 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135624

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: 0.0000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000645 AC: 93 AN: 1441558 Hom.: 0 Cov.: 27 AF XY: 0.0000612 AC XY: 44 AN XY: 718684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000823

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74308

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: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:9 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 85 of the CFTR protein (p.Gly85Glu). This variant is present in population databases (rs75961395, gnomAD 0.009%). This missense change has been observed in individuals with cystic fibrosis and other CFTR-related conditions (PMID: 1710599, 9271620, 15176679, 19885835, 22020151, 23891399, 23974870). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7143). 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: 21998193). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 15, 2019	NM_000492.3(CFTR):c.254G>A(G85E) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.254G>A(G85E) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 27, 2022	The p.G85E pathogenic mutation (also known as c.254G>A), located in coding exon 3 of the CFTR gene, results from a G to A substitution at nucleotide position 254. The glycine at codon 85 is replaced by glutamic acid, an amino acid with similar properties. This mutation was first described in a pancreatic insufficient individual with cystic fibrosis with a second CFTR mutation in trans (Zielenski J et al. Genomics, 1991 May;10:229-35). This mutation results in failure of protein maturation and chloride conductance, and is associated with a severe disease phenotype (Decaestecker K et al. Eur. Respir. J., 2004 May;23:679-84; Gené GG et al. Hum. Mutat., 2008 May;29:738-49). In a cohort of 201 patients with this mutation, elevated sweat chloride levels, pulmonary disease, and pancreatic insufficiency were reported in the majority of individuals (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1991	- -

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 24, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 27, 2021	This variant has been reported in individuals affected with Cystic Fibrosis and Cystic Fibrosis Related Disorders (CFRD) in the published literature (PMID: 32429104 (2020), 28603918 (2017), 23891399 (2014), 23974870 (2013), 23951356 (2013), 22658665 (2012), 22020151 (2012), 18456578 (2008)). In addition, this variant has been shown to have a damaging effect on CFTR protein function (PMID: 32204475 (2020), 24440181 (2014), 23891399 (2014), 15176679 (2004)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 25, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2019	The CFTR c.254G>A; p.Gly85Glu variant (rs75961395) is reported in multiple unrelated patients diagnosed with cystic fibrosis (Chalkley 1991, Chavez-Saldana 2010, Gallati 2009, Kerem 1997, Ooi 2012, Zielenski 1991, CFTR2 database). However, the clinical presentations of these patients are highly variable, ranging from severe lung disorder and pancreatic insufficiency, to mild respiratory symptoms and pancreatic sufficiency (Chalkley 1991, Kerem 1997). Functional characterization of the variant protein indicates a failure in trafficking to the cell surface (Patrick 2011, Sosnay 2013, Van Goor 2014), due to aberrant integration of the protein in the endoplasmic reticulum (Patrick 2011). The variant is described in the ClinVar database (Variation ID: 7143) and in the Genome Aggregation Database in 12 out of 276578 alleles. The glycine at residue 85 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has a deleterious impact on the protein. Considering available information, the variant is classified as pathogenic. References: Link to CFTR2 database: http://cftr2.org/ Chalkley G et al. A cystic fibrosis patient who is homozygous for the G85E mutation has very mild disease. J Med Genet. 1991 28(12):875-7. Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010 62(6):546-52. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 19(5):685-94. Kerem B et al. A missense cystic fibrosis transmembrane conductance regulator mutation with variable phenotype. Pediatrics. 1997 100(3):E5. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. Patrick A et al. Alteration of CFTR transmembrane span integration by disease-causing mutations. Mol Biol Cell. 2011 22(23):4461-71. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 13(1):29-36. Zielenski J et al. Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1991 May;10(1):229-35. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

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

Mar 14, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.4	D;D;.;.;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;.;.;D;.
Polyphen		0.99	.;D;.;.;.;.
Vest4		0.97
MVP		1.0
MPC		0.012
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs75961395; hg19: chr7-117149177;