rs145545286

Positions:

chr7-117664727-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000492.4(CFTR):c.4003C>T(p.Leu1335Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,910 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1335P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 2.42

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 Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a domain ABC transporter 2 (size 233) in uniprot entity CFTR_HUMAN there are 28 pathogenic changes around while only 3 benign (90%) 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 chr7-117664728-T-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.4003C>T	p.Leu1335Phe	missense_variant	25/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.4003C>T	p.Leu1335Phe	missense_variant	25/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251130

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727180

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000290

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2018	The CFTR c.4003C>T; p.Leu1335Phe variant (rs145545286) is reported in the literature in the heterozygous state with an unknown second allele in individuals with a suspected diagnosis of cystic fibrosis, as well as in healthy carriers (Krenkova 2013, Picci 2010, Tabor 2014). This variant is reported in ClinVar (Variation ID: 53871), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 1335 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.4004T>C p.Leu1335Pro) has been reported in individuals with cystic fibrosis and is considered mildly pathogenic (Ahmed 2003, Raraigh 2018, CFTR2 database). However, given the lack of clinical and functional data, the significance of the p.Leu1335Phe variant is uncertain at this time. References: Link to CFTR2 database for p.Leu1335Pro: https://cftr2.org/mutation/scientific/pi/L1335P Ahmed N et al. Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas. Gut. 2003 Aug;52(8):1159-64. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. Picci L et al. A 10-year large-scale cystic fibrosis carrier screening in the Italian population. J Cyst Fibros. 2010 Jan;9(1):29-35. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Tabor HK et al. Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. Am J Hum Genet. 2014 Aug 7;95(2):183-93. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2023	Variant summary: CFTR c.4003C>T (p.Leu1335Phe) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) 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 8.2e-06 in 367128 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4003C>T has been reported in the literature in individuals with Cystic Fibrosis with non informative genotype (Krenkova_2009, Krenkova_2013), in a COPD study (Saferali_2022) and in context of new born screening (Tabor_2014). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another variant affecting the same amino acid (p.Leu1335Pro) has been classified in our lab as pathogenic, however the evidence is limited at this time to allow any conclusions for the role of this variant in disease. The following publications have been ascertained in the context of this evaluation (PMID: 12865275, 19897426, 20163773, 23276700, 34996830, 25087612). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cystic fibrosis

Uncertain:1Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 2022	The p.L1335F variant (also known as c.4003C>T), located in coding exon 25 of the CFTR gene, results from a C to T substitution at nucleotide position 4003. The leucine at codon 1335 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was identified in Czech cohort of individuals with cystic fibrosis; however, additional information was limited (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). In addition, it was also identified in an Italian cohort of individuals undergoing carrier screening (Picci L et al. J. Cyst. Fibros., 2010 Jan;9:29-35). 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 available evidence to date, the clinical significance of this alteration remains unclear. -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 30, 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.3

M;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.4

D;D;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0040

D;D;.

Sift4G

Uncertain

0.0070

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.92

MVP

1.0

MPC

0.016

ClinPred

0.96

GERP RS

5.6

Varity_R

0.72

gMVP

0.88

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