rs397508658
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):c.4004T>C(p.Leu1335Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,748 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: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
CFTR
NM_000492.4 missense
NM_000492.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.52
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 7-117664728-T-C is Pathogenic according to our data. Variant chr7-117664728-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 53872.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117664728-T-C is described in Lovd as [Pathogenic]. Variant chr7-117664728-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.4004T>C | p.Leu1335Pro | missense_variant | 25/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.4004T>C | p.Leu1335Pro | missense_variant | 25/27 | 1 | NM_000492.4 | ENSP00000003084.6 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461748Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727186
GnomAD4 exome
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5
AN:
1461748
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32
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4
AN XY:
727186
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:9Uncertain:1
Likely pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 3 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_STR, PM5, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 08, 2020 | The p.L1335P pathogenic mutation (also known as c.4004T>C), located in coding exon 25 of the CFTR gene, results from a T to C substitution at nucleotide position 4004. The leucine at codon 1335 is replaced by proline, an amino acid with similar properties. This mutation was identified in two pancreatic sufficient individuals with cystic fibrosis (CF) in conjunction with p.F508del (Rose JB et al. Clin. Biochem., 2009 Aug;42:1260-4; Ivanov M et al. BMC Med Genomics, 2018 02;11:13). It has also been reported in cohorts of individuals with CF; however, specific genotype and phenotype information was not provided (Scotet V et al. Hum. Mutat., 2003 Jul;22:105; Ahmed N et al. Gut, 2003 Aug;52:1159-64; Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). Functional analysis of this variant in CFBE cells demonstrated 2% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 27, 2016 | The CFTR c.4004T>C (p.Leu1335Pro) variant is a missense variant that has been reported in four studies, where it was found in a heterozygous state in a total of six individuals with cystic fibrosis; no second variant was identified in these individuals (Scotet et al. 2003; Krenkova et al. 2009; Dorfman et al. 2010; Krenkova et al. 2013). Control data are unavailable for the p.Leu1335Pro variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium despite being found in a region of good sequencing coverage. The variant is thus presumed to be rare. The evidence for this variant is limited. Therefore, the p.Leu1335Pro variant is classified as a variant of unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 10, 2024 | Variant summary: CFTR c.4004T>C (p.Leu1335Pro) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) and AAA+ ATPase domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251130 control chromosomes (gnomAD). c.4004T>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Rose_2009, Masica_2015, Ivanov_2018, McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a loss of CFTR function (Han_2018). The following publications have been ascertained in the context of this evaluation (PMID: 12815607, 20059485, 15390350, 20163773, 20932301, 23276700, 25489051, 19445912, 29504914, 19734129, 30888834, 30046002). ClinVar contains an entry for this variant (Variation ID: 53872). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 03, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1335 of the CFTR protein (p.Leu1335Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cystic fibrosis (PMID: 19445912, 23974870, 29504914). ClinVar contains an entry for this variant (Variation ID: 53872). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Mar 06, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 23, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 29, 2018 | - - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Dec 08, 2017 | - - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 23, 2019 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 02, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.
Sift4G
Pathogenic
D;D;.
Polyphen
D;.;.
Vest4
MutPred
Loss of stability (P = 0.0294);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at