rs387906368
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000492.4(CFTR):c.1601C>A(p.Ala534Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,607,338 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. A534S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1601C>A | p.Ala534Glu | missense_variant | 12/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1601C>A | p.Ala534Glu | missense_variant | 12/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250864Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135570
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1455100Hom.: 0 Cov.: 28 AF XY: 0.00000828 AC XY: 6AN XY: 724376
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74426
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 01, 2022 | The p.A534E variant (also known as c.1601C>A), located in coding exon 12 of the CFTR gene, results from a C to A substitution at nucleotide position 1601. The alanine at codon 534 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration was identified in an individual with a clinical diagnosis of cystic fibrosis however no further details were provided (Rueda-Nieto S et al. Orphanet J Rare Dis, 2022 06;17:222). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 534 of the CFTR protein (p.Ala534Glu). This variant is present in population databases (rs387906368, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 35698092). ClinVar contains an entry for this variant (Variation ID: 7173). 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 not 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 09, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 27, 2021 | - - |
not specified Uncertain:1
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.1601C>A (p.Ala534Glu) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250864 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1601C>A has been reported in the literature as a compound heterozygous genotype and as an uninformative genotype (i.e. zygosity and/or second variant not specified) in individuals affected with Cystic Fibrosis (Audrezet_1993, Rueda-Nieto_2022). These data do not allow any conclusion about variant significance. 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: 7683952, 35698092). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as VUS. 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 | Mar 06, 2022 | - - |
CFTR-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 28, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at