rs1800089

Positions:

chr7-117559470-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000492.4(CFTR):c.1399C>T(p.Leu467Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000025 in 1,601,010 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L467P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:7B:3O:1

Conservation

PhyloP100: 4.61

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:

CFTR-AS1 (HGNC:):

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) 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 chr7-117559471-T-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1399C>T	p.Leu467Phe	missense_variant	11/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS1	NR_149084.1 linkuse as main transcript	n.221+1263G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1399C>T	p.Leu467Phe	missense_variant	11/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152118

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251216

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135790

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:

0.0000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000214

AC:

AN:

1448892

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

721796

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:

0.0000273

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74318

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000764

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:7Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:3Uncertain:2Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 22, 2017	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 4 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: PS3_SUP, PM2_SUP, PM3, PP3, PP4 -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 22, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 04, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 467 of the CFTR protein (p.Leu467Phe). This variant is present in population databases (rs1800089, gnomAD 0.009%). This variant has been observed in several individuals affected with CFTR-related conditions (PMID: 16436643, 29271547, 21783433, 10923036, 26436105, 27917292, 24106596, 19202204, 29504914). However, in most of these individuals this variant was observed in cis with a pathogenic allele, which suggests that this c.1399C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 53246). 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: 29271547). This variant disrupts the p.Leu467 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20510657, 23891399, 23974870, 26708955). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	CFTR: PS4:Moderate, PP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 16, 2021	- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Feb 15, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 20, 2024

Variant summary: CFTR c.1399C>T (p.Leu467Phe) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251294 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (4e-05 vs 0.013), allowing no conclusion about variant significance. c.1399C>T has been reported in the literature in individuals affected with Cystic Fibrosis as well as CFTR-related disorders, however, often a second allele is not specified. In addition, the variant has been reported in multiple patients in cis with the common pathogenic mutation F508del, in both internal samples and reported in the literature (e.g. Vecchio-Pagan_2016, Costa_2011, Sermet-Gaudelus_2010, Terlizzi_2020, Kondratyeva_2022), suggesting the variant may be benign. The variant has also been reported in an internal sample with two pathogenic mutations, providing additional supporting evidence for a benign role. However, recent cases and functional evidence has suggested that p.Leu467Phe, as part of a complex allele with F508del, may impact patient response to CFTR modulators, although it does not necessarily increase the severity of disease symptoms (Kondratyeva_2022, Sondo_2022). In a cell-based functional study, CFTR-p.Leu467Phe tested alone had a significantly reduced maturation compared to CFTR-WT and a reduced channel activity (Baatallah_2018). However, the impact of this variant in relation to human disease remains unclear. The following publications have been ascertained in the context of this evaluation (PMID: 20538955, 36286063, 32292813, 32026723, 32150665, 29271547, 27917292, 26436105, 28603918, 26437683, 36142302, 21783433, 22892530, 24106596, 22020151, 16436643, 19202204, 10923036, 18716917, 35328596, 38388235, 35365085). ClinVar contains an entry for this variant (Variation ID: 53246). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2024

The CFTR c.1399C>T variant is predicted to result in the amino acid substitution p.Leu467Phe. This variant has been reported along with p.Phe508del in a non-affected individual (Sobczyriska-Tomaszewska et al. 2013. PubMed ID: 22892530). It has been reported in the heterozygous state in individuals with cystic fibrosis or cystic fibrosis related disorders, without indication of a second pathogenic variant (Elahi et al. 2006. PubMed ID: 16436643; Amato et al. 2011. PubMed ID: 22020151). This variant has been reported as a complex allele (variants in cis on the same allele) with p.Phe508del in individuals with cystic fibrosis. Some of these individuals the complex allele was present alone and in other cases p.Phe508del was found in trans on the other allele (Raraigh et al. 2021. PubMed ID: 34782259; Petrova et al. 2022. PubMed ID: 35365085). There was no difference in disease severity when comparing patients with the complex allele to those who were homozygous for p.Phe508del (Petrova et al. 2022. PubMed ID: 35365085). Minigene analysis using HEK293 cells showed this variant affects protein maturation and channel activity, and also demonstrated that p.Phe508del alone recovers with corrector/potentiator treatment; however, this same treatment was ineffective for the complex allele (Baatallah et al. 2018. PubMed ID: 29271547). An alternate nucleotide change affecting the same amino acid (p.Leu467Pro) has been reported to be pathogenic (Sosnay et al. 2013. PubMed ID: 23974870; Internal Data, PreventionGenetics). This variant is reported in 0.0085% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant has conflicting classifications in ClinVar ranging from likely benign to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/53246/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;.;D;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.81

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.8

L;.;.;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.7

D;.;.;D;.

REVEL

Pathogenic

0.79

Sift

Benign

0.079

T;.;.;T;.

Sift4G

Uncertain

0.0030

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.95

MVP

1.0

MPC

0.0091

ClinPred

0.41

GERP RS

5.5

Varity_R

0.80

gMVP

0.97

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