rs397508498
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):c.3107C>A(p.Thr1036Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,434 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. T1036I) has been classified as Likely 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.3107C>A | p.Thr1036Asn | missense_variant | 19/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3107C>A | p.Thr1036Asn | missense_variant | 19/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.177+5592G>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152098Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250950Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135624
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461336Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726962
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152098Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74286
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:5Other:1
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 15, 2021 | The p.T1036N variant (also known as c.3107C>A), located in coding exon 19 of the CFTR gene, results from a C to A substitution at nucleotide position 3107. The threonine at codon 1036 is replaced by asparagine, an amino acid with similar properties. This variant was reported in a homozygous individual with a classic presentation of cystic fibrosis (McGinniss MJ et al. Hum Genet, 2005 Dec;118:331-8). This variant was also reported in trans with p.F508del mutation in an individual with classic cystic fibrosis (Petrova NV et al. Genes (Basel), 2020 05;11:). Additionally, this variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 10/14/2021). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
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: PM2_SUP, PM3_STR, PM5, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 25, 2022 | Variant summary: CFTR c.3107C>A (p.Thr1036Asn) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain 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 250950 control chromosomes. c.3107C>A has been reported in the literature as a biallelic compound heterozygous or homozygous genotype in multiple individuals affected with Cystic Fibrosis (example, Giusti_2007, McGinniss_2005, Salinas_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and an expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 11, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 16, 2023 | 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CFTR protein function. This variant disrupts the p.Thr1036 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 17662673), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1036 of the CFTR protein (p.Thr1036Asn). This variant is present in population databases (rs397508498, gnomAD 0.004%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 16189704, 27214204, 32429104). 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: 53652). - |
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 21, 2019 | The CFTR c.3107C>A; p.Thr1036Asn variant (rs397508498) is reported in the literature in individuals affected with either pancreatic-sufficient or pancreatic-insufficient cystic fibrosis (CF) (Chavez-Saldana 2010, McGinniss 2005, Salinas 2016). This variant has been identified in affected individuals both in the homozygous state (McGinniss 2005) and in heterozygous individuals with an additional pathogenic variant (Salinas 2016). This variant is found on only two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 1036 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at the same codon (p.Thr1036Ile) has been reported in individuals with CF and is considered pathogenic (Alibakhshi 2008, Sahami 2014). Based on available information, the p.Thr1036Asn variant is considered to be likely pathogenic. References: Alibakhshi R et al. Analysis of the CFTR gene in Iranian cystic fibrosis patients: identification of eight novel mutations. J Cyst Fibros. 2008 Mar;7(2):102-9. Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010 Nov-Dec;62(6):546-52. McGinniss MJ et al. Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. Hum Genet. 2005 Dec;118(3-4):331-8. Sahami A et al. Mutation Analysis of Exons 10 and 17a of CFTR Gene in Patients with Cystic Fibrosis in Kermanshah Province, Western Iran. J Reprod Infertil. 2014 Jan;15(1):49-56. Salinas DB et al. Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. PLoS One. 2016 May 23;11(5):e0155624. - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 02, 2021 | PM2, PM3_strong - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 14, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at