rs397508139
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):c.1007T>A(p.Ile336Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,844 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. I336?) has been classified as Pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1007T>A | p.Ile336Lys | missense_variant | 8/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1007T>A | p.Ile336Lys | missense_variant | 8/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251238Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135780
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461844Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727218
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:8
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_MOD, PM2_SUP, PM3_STR, PP3, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jul 07, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 336 of the CFTR protein (p.Ile336Lys). This variant is present in population databases (rs397508139, gnomAD 0.0009%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7508414, 9272157, 19318346, 24586523). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53162). 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: 23891399, 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Feb 13, 2023 | Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 07, 2022 | The p.I336K pathogenic mutation (also known as c.1007T>A), located in coding exon 8 of the CFTR gene, results from a T to A substitution at nucleotide position 1007. The isoleucine at codon 336 is replaced by lysine, an amino acid with dissimilar properties. This pathogenic mutation has been reported in multiple cystic fibrosis (CF) patients who have a second pathogenic mutation in trans. This mutation is associated with elevated sweat chloride levels, decreased lung function, and Pseudomonas infection; CF patients with this mutation are more likely to be pancreatic sufficient (Sosnay PR, Nat. Genet. 2013 Oct; 45(10):1160-7, Supplementary Table). In addition, a functional study of this mutation demonstrated that this alteration significantly decreases the amount of normal mature CFTR protein and chloride transport activity compared to the wild-type allele (Van Goor F, J. Cyst. Fibros. 2014; 13(1):29-36). Based on the supporting evidence, p.I336K is interpreted as a disease-causing mutation. - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 15, 2023 | The CFTR c.1007T>A (p.Ile336Lys) variant has been reported in the published literature in individuals with cystic fibrosis (PMID: 7508414 (1993), 7505690 (1993), 19318346 (2009), 24586523 (2014)). This variant has also been reported in cystic fibrosis related disorders including congenital bilateral absence of the vas deferens (CBAVD) (PMID: 9272157 (1997)) and pancreatitis (PMID: 10950058 (2000)). Published functional studies showed that this variant affects CFTR protein function (PMID: 23974870 (2013), 23891399 (2014), 29805046 (2018), 30046002 (2018)). The frequency of this variant in the general population, 0.000004 (1/251238 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 15, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 05, 2021 | PP3, PP5, PM2, PM3_very_strong, PS3 - |
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 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 18, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at