rs397508670
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000492.4(CFTR):c.4091C>T(p.Ala1364Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,954 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A1364A) has been classified as Likely benign.
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.4091C>T | p.Ala1364Val | missense_variant | 25/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.4091C>T | p.Ala1364Val | missense_variant | 25/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152106Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251250Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135778
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461730Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727180
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74414
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:5Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 05, 2022 | The p.A1364V variant (also known as c.4091C>T), located in coding exon 25 of the CFTR gene, results from a C to T substitution at nucleotide position 4091. The alanine at codon 1364 is replaced by valine, an amino acid with similar properties. This variant was reported in conjunction with p.F508del in an individual with congenital absence of the vas deferens (CBAVD) (de Meeus A et al. Hum. Mutat., 1998;11:480). This amino acid position is highly 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. - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 04, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1364 of the CFTR protein (p.Ala1364Val). This variant is present in population databases (rs397508670, gnomAD 0.02%). This missense change has been observed in individuals with congenital bilateral absence of vas deferens and/or pancreatitis (PMID: 10200050, 17003641, 21520337). ClinVar contains an entry for this variant (Variation ID: 53885). 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 13, 2023 | The CFTR c.4091C>T; p.Ala1364Val variant (rs397508670) is reported in the literature in two individuals affected with CBAVD co-occurring with another pathogenic CFTR variant (de Meeus 1998, Luo 2021). In addition, this variant had been reported as heterozygous in an individual with pancreatitis (Keiles 2006). This variant is also reported in ClinVar (Variation ID: 53885). This variant is found in the general population with an allele frequency of 0.004% (9/251250 alleles) in the Genome Aggregation Database. The alanine at codon 1364 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.754). However, given the lack of clinical and functional data, the significance of the p.Ala1364Val variant is uncertain at this time. References: de Meeus A et al. Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online. Hum Mutat. 1998;11(6):480. PMID: 10200050. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Luo S et al. Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. Gene. 2021 Jan 10;765:145045. PMID: 32777524. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 20, 2022 | PP3, PM2 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 18, 2023 | Variant summary: CFTR c.4091C>T (p.Ala1364Val) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) 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 3.9e-05 in 255050 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (3.9e-05 vs 0.013), allowing no conclusion about variant significance. c.4091C>T has been reported in the literature as a compound heterozygous genotype with p.F508del in at-least one individual affected with CAVD (example, deMeeus_1997) or in the absense of a second variant (example, Luo_2021). It has also been reported in heterozygote inviduals affected with pancreatitis (example, Keiles_2006) or with a CF-like disorder associated with AGR2 mutations, in which the patient had a negative sweat chloride test (Bertolli-Avella_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: 17003641, 20059485, 21520337, 22483971, 11504857, 10200050, 25735457, 26277102, 25880441, 32777524, 34740355, 34952832, 35913788). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance (n=6). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary pancreatitis Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
CFTR-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 15, 2023 | The CFTR c.4091C>T variant is predicted to result in the amino acid substitution p.Ala1364Val. This variant is predicted to generate a cryptic splicing donor site based on available splicing prediction programs (Alamut Visual Plus v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. This variant has been reported in the heterozygous state in multiple individuals with congenital absence of vas deferens, and in one individual was reported along with a p.Phe508del variant (de Meeus et al. 1997. PubMed ID: 10200050; Supporting Table S5, Steiner et al. 2011. PubMed ID: 21520337; Table 1, Luo et al. 2020. PubMed ID: 32777524). This variant has also been reported in the heterozygous state in an individual with pancreatitis (Table 2, Keiles et al. 2006. PubMed ID: 17003641). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117304869-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at