rs150691494
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000492.4(CFTR):āc.902A>Gā(p.Tyr301Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000201 in 1,613,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00020 ( 0 hom., cov: 32)
Exomes š: 0.00020 ( 0 hom. )
Consequence
CFTR
NM_000492.4 missense
NM_000492.4 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 5.24
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 Uncertain_significance. Variant got 2 ACMG points.
PM1
In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13123178).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.902A>G | p.Tyr301Cys | missense_variant | Exon 8 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000197 AC: 30AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000291 AC: 73AN: 250950Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135664
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GnomAD4 exome AF: 0.000201 AC: 294AN: 1461060Hom.: 0 Cov.: 30 AF XY: 0.000219 AC XY: 159AN XY: 726886
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GnomAD4 genome AF: 0.000197 AC: 30AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74344
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 15, 2023 | BP2, PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 15, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 15, 2024 | The CFTR c.902A>G; p.Tyr301Cys variant (rs150691494, ClinVar Variation ID: 198738) is reported in the literature in individuals with cystic fibrosis or related symptoms (El-Seedy 2016, Krenkova 2013) and in several newborns with hypertrypsinemia or a positive newborn screen but also normal sweat chloride (Castellani 1999, Ooi 2015, Scotet 2001). This variant is found in the Ashkenazi Jewish population with an allele frequency of 0.42% (44/10364 alleles) in the Genome Aggregation Database (v2.1.1). The tyrosine at codon 301 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.86). However, given the lack of clinical and functional data, the significance of the p.Tyr301Cys variant is uncertain at this time. References: Castellani C et al. Cystic fibrosis mutations in heterozygous newborns with hypertrypsinemia and low sweat chloride. Am J Hum Genet. 1999 Jan;64(1):303-4. PMID: 9915972. El-Seedy A et al. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations in North Egyptian population: implications for the genetic diagnosis in Egypt. Cell Mol Biol (Noisy-le-grand). 2016 Nov 30;62(13):21-28. PMID: 28040058. 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. PMID: 23276700. Ooi CY et al. Inconclusive diagnosis of cystic fibrosis after newborn screening. Pediatrics. 2015 Jun;135(6):e1377-85. PMID: 25963003. Scotet V et al. Prevalence of CFTR mutations in hypertrypsinaemia detected through neonatal screening for cystic fibrosis. Clin Genet. 2001 Jan;59(1):42-7. PMID: 11168024. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 19, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2017 | The Y301C variant in the CFTR gene has been reported previously in individuals with an additional variant in CFTR who screened positive for cystic fibrosis on newborn screening; however, these individuals had inconclusive diagnosis with normal sweat chloride levels at followup (Castellani et al., 1999; Ooi et al., 2015). The Y301C variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y301C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R297W, A299T) have been reported in the Human Gene Mutation Database in association with CFTR-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Y301C as a variant of uncertain significance. - |
Cystic fibrosis Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2023 | The p.Y301C variant (also known as c.902A>G), located in coding exon 8 of the CFTR gene, results from an A to G substitution at nucleotide position 902. The tyrosine at codon 301 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in two newborns with an elevated immunoreactive trypsinogen (IRT) and normal sweat chloride levels, who were also heterozygous for p.F508del (Castellani C et al. Am. J. Hum. Genet., 1999 Jan;64:303-4; Ooi CY et al. Pediatrics, 2015 Jun;135:e1377-85). This variant was detected as heterozygous in a newborn with cystic fibrosis-related metabolic syndrome and in 1/177 CF and CFTR-related patients, but a second CFTR alteration was not detected in these patients (Trujillano D et al. Mol Genet Genomic Med, 2015 Sep;3:396-403; Baaran AE et al. Turk J Med Sci, 2019 Dec;49:1655-1661). In another study, this variant was identified in an individual with cystic fibrosis; however, complete genotype and phenotype information was not provided (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). This alteration was also identified in an individual with asthma and an individual with lung cancer (Tzetis M et al. Hum. Genet., 2001 Mar;108:216-21; Bombieri C et al. Hum. Genet., 1998 Dec;103:718-22). This variant was also detected in 1/1279 Sicilian infertile patients who underwent CFTR screening (Chamayou S et al. BMC Med Genet, 2020 May;21:89). This amino acid position is well 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. - |
Uncertain significance, criteria provided, single submitter | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 23, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 301 of the CFTR protein (p.Tyr301Cys). This variant is present in population databases (rs150691494, gnomAD 0.5%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9921909, 11303517, 11354633, 23276700, 28040058). ClinVar contains an entry for this variant (Variation ID: 198738). 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. 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. - |
CFTR-related disorder Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 30, 2017 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2024 | Variant summary: CFTR c.902A>G (p.Tyr301Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 0.00029 in 251692 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00029 vs 0.013), allowing no conclusion about variant significance. c.902A>G has been reported in the literature in sequencing/genotyping studies, as examples, 1. with p.F508del in a neonate with raised immunoreactive trypsinogen concentration (IRT) and low sweat chloride (18 mEq/liter), 2. in a patient in low sweat chloride (<30 mmol/L) and an inconclusive diagnosis of CF (Castellani_1999, Ooi_2015), 3. as a non-informative genotype in patients with asthama (Tzetis_2001), lung cancer (Bombieri_1998), infertility (Chamayou_2020), unaffected carriers (Scotet_2001), settings of diagnostic CF genotyping (Wei_2006, Krenkova_2012, Trujillano_2015, El-Seedy_2016), 4. with other CFTR variants in patients/newborns lacking sufficient clinical evidence (Schwartz_2009, Poulou_2014, Olsowiec-Chlebna_2021). 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. The following publications have been ascertained in the context of this evaluation (PMID: 9921909, 9915972, 11303517, 32357917, 28040058, 23276700, 33836782, 25963003, 24784896, 19324992, 11168024, 26436105, 11354633, 16617247, 36409994). ClinVar contains an entry for this variant (Variation ID: 198738). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
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 | May 18, 2022 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 16, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;D;.
REVEL
Pathogenic
Sift
Benign
T;.;.;T;.
Sift4G
Uncertain
D;.;.;D;.
Polyphen
D;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at