rs121909020
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000492.4(CFTR):c.3199G>A(p.Ala1067Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,442 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 drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1067V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3199G>A | p.Ala1067Thr | missense_variant | 20/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3199G>A | p.Ala1067Thr | missense_variant | 20/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.177+4589C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152086Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250886Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135588
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461356Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 726956
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152086Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74284
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2023 | The p.A1067T variant (also known as c.3199G>A), located in coding exon 20 of the CFTR gene, results from a G to A substitution at nucleotide position 3199. The alanine at codon 1067 is replaced by threonine, an amino acid with similar properties. This variant was originally reported to be in trans with p.F508del in a child with cystic fibrosis (Férec C et al. Nat. Genet., 1992 Jun;1:188-91). Multiple studies demonstrated that this variant impairs CFTR maturation and function (Cotten JF et al. J. Biol. Chem., 1996 Aug;271:21279-84; Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). However, p.A1067T has never been observed in isolation and always co-occurred with p.F508del, and segregation analysis determined that the two variants are in cis and form a complex allele, p.[F508del;A1067T] (Culard JF et al. Hum. Genet., 1994 Apr;93:467-70; de Meeus A et al. Hum. Mutat., 1998;11:480; Claustres M et al. Hum Mutat, 2017 10;38:1297-1315; Ambry internal data). This amino acid position is highly 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1992 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2021 | This sequence change replaces alanine with threonine at codon 1067 of the CFTR protein (p.Ala1067Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with cystic fibrosis and pancreatic insufficiency and in an individual with congenital bilateral aplasia of vas deferens, both of whom also were found to have a p.Phe508del variant in CFTR. In at least one instance, this variant has been reported to occur on the same chromosome as p.Phe508del (PMID: 1284639, 10200050). ClinVar contains an entry for this variant (Variation ID: 7159). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 8662892, 8702904, 11242048, 23891399, 28003367). This variant disrupts the p.Phe508 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1284639, 10200050). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 16, 2024 | Variant summary: CFTR c.3199G>A (p.Ala1067Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 4e-06 in 250886 control chromosomes (gnomAD). c.3199G>A has been reported in the literature in an individual affected with Cystic Fibrosis who had F508del in trans (Ferec_1992). In other patients with Cystic Fibrosis or CBAVD, the variant was found in cis with p.F508del (e.g. Culard_1994, de Meeus_1998, Claustres_2017, Raraigh_2022). These data do not allow any conclusion about variant significance. Publications report experimental evidence evaluating an impact on protein function (Cotten_1996, Seibert_1996, van Goor_2014), finding that the variant results in reduced mature CFTR protein and impaired channel function. The following publications have been ascertained in the context of this evaluation (PMID: 1284639, 23891399, 34782259, 10200050, 8662892, 8702904, 7513294, 28603918). ClinVar contains an entry for this variant (Variation ID: 7159). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 11, 2016 | - - |
CFTR-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 05, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 16, 2013 | - - |
ivacaftor response - Efficacy Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at