rs397508442

Positions:

chr7-117603708-C-T

Variant summary

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

The NM_000492.4(CFTR):c.2834C>T(p.Ser945Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,614,012 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. S945S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:19O:1

Conservation

PhyloP100: 7.71

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 7-117603708-C-T is Pathogenic according to our data. Variant chr7-117603708-C-T is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 53575.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117603708-C-T is described in Lovd as [Pathogenic]. Variant chr7-117603708-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2834C>T	p.Ser945Leu	missense_variant	17/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2834C>T	p.Ser945Leu	missense_variant	17/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251404

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000243

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000554

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:19Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 13, 2022	The p.S945L pathogenic mutation (also known as c.2834C>T), located in coding exon 17 of the CFTR gene, results from a C to T substitution at nucleotide position 2834. The serine at codon 945 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In one study, this mutation was detected in an infant with pulmonary disease, pancreatic insufficiency, a sweat chloride level of 58, and p.F508del confirmed in trans (Feldmann D et al. Hum. Mutat., 2003 Oct;22:340). This mutation was found to decrease the amount of full mature protein and is suspected to interfere with chloride permeability in the CFTR channel (Seibert FS et al. J. Biol. Chem., 1996 Nov;271:27493-9). This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency in 40% of individuals, and Pseudomonas infection in half of individuals; in vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition, in the heterozygous state, this mutation has been observed to be contributory to a pancreatitis phenotype (Masson E et al. PLoS ONE, 2013 Aug;8:e73522). Based on the supporting evidence, p.S945L is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2019	Variant summary: CFTR c.2834C>T (p.Ser945Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain 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 7.6e-05 in 277138 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (7.6e-05 vs 0.013), allowing no conclusion about variant significance. c.2834C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. One ClinVar submission from PharmGKB reports the variant to have a drug response. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Oct 02, 2020	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	May 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 945 of the CFTR protein (p.Ser945Leu). This variant is present in population databases (rs397508442, gnomAD 0.03%). This missense change has been observed in individuals with cystic fibrosis (PMID: 16189704, 19318346, 21354377, 29279204, 29504914). ClinVar contains an entry for this variant (Variation ID: 53575). 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: 22545782, 23891399, 29279204). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient 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: PS3_SUP, PM2_SUP, PM3_STR, PP3, PP4 -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Apr 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2019	The CFTR c.2834C>T; p.Ser945Leu variant (rs397508442) is reported in the literature in multiple individuals affected with either pancreatic sufficient or pancreatic insufficient cystic fibrosis (CF) (see link to CFTR2 database, Sosnay 2013), and also in a few individuals affected with CFTR-related disorders who carry a second pathogenic-mild variant or no reported second variant (Masvidal 2009, Masson 2013). The p.Ser945Leu variant is reported in ClinVar (Variation ID: 53575), and is found in the general population with an overall allele frequency of 0.0071% (20/282808 alleles) in the Genome Aggregation Database. The serine at codon 945 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show reduced processing, maturation and chloride transport activity (Sosnay 2013, Van Goor 2014). Both in vitro and in vivo functional analyses demonstrate a positive response to drug treatment for CF patients (Kim 2018, Van Goor 2014). Based on available information, this variant is considered to be pathogenic. References: Link to CFTR2 database: https://cftr2.org/ Claustres M et al. Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in southern France. Hum Mol Genet. 1993 Aug;2(8):1209-13. Kim J et al. Ivacaftor restores CFTR-dependent sweat gland fluid secretion in cystic fibrosis subjects with S945L alleles. J Cyst Fibros. 2018 Mar;17(2):179-185. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 8(8):e73522. Masvidal L et al. The p.Arg258Gly mutation in intracellular loop 2 of CFTR is associated with CFTR-related disorders. Genet Test Mol Biomarkers. 2009 13(6):765-8. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 28, 2021	PS3, PM3_strong,, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 04, 2022	The frequency of this variant in the general population, 0.00032 (8/25116 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with cystic fibrosis and pancreatic insufficiency (Cystic Fibrosis Mutation Database (www.genet.sickkids.on.ca/app), CFTR2 (www.cftr2.org), PMIDs: 32429104 (2020), 28801929 (2017), 23891399 (2014), 23974870 (2013), 12955726 (2003), and 7691344 (1993)). Functional studies found that this variant caused misprocessing and decreased chloride transport (PMIDs: 16196493 (2005) and 23891399 (2014)). 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;na:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

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.

May 20, 2019

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 01, 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

0.83

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.1

H;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.6

D;.;.;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.91

MutPred

0.91

Gain of ubiquitination at K946 (P = 0.0934);.;.;.;.;

MVP

1.0

MPC

0.017

ClinPred

0.99

GERP RS

5.8

Varity_R

0.97

gMVP

0.98

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