chr7-117611641-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000492.4(CFTR):c.3200C>T(p.Ala1067Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,382 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3200C>T | p.Ala1067Val | missense_variant | Exon 20 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152044Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250938Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135618
GnomAD4 exome AF: 0.0000773 AC: 113AN: 1461338Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 52AN XY: 726970
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152044Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74264
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:2Uncertain:3
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This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1067 of the CFTR protein (p.Ala1067Val). This variant is present in population databases (rs1800114, gnomAD 0.003%). This missense change has been observed in individuals with congenital bilateral absence of the vas deferens and cystic fibrosis (PMID: 7539342, 7689902, 8556303; Invitae). ClinVar contains an entry for this variant (Variation ID: 53683). 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 with a positive predictive value of 80%. This variant disrupts the p.Ala1067 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 1284639, 8662892, 8702904, 23891399, 27131402), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
The p.A1067V variant (also known as c.3200C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3200. The alanine at codon 1067 is replaced by valine, an amino acid with similar properties. This variant has been detected in conjunction with a pathogenic CFTR mutation in individuals with congenital bilateral absence of the vas deferens (CBAVD), with no or few other signs of cystic fibrosis; however, the phase of the alterations (cis or trans) was not reported (De Braekeleer M et al. Mol. Hum. Reprod.,1996 Sep;2:669-77; Jézéquel P et al. Mol Hum Reprod, 2000 Dec;6:1063-7). Based on internal structural analysis, this variant is more destabilizing than known pathogenic variants within the domain (Jin MS et al. Nature, 2012 Oct;490:566-9). 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 the available evidence, the clinical significance of this variant remains unclear. -
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not provided Pathogenic:1Uncertain:3
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Observed in individuals with congenital absence of the vas deferens who also harbored additional CFTR variants, but segregation data and additional clinical information was not included (PMID: 9239681, 7539342, 8556303, Woods, 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24419263, 7689902, 7539342, 25087612, 1284534, Woods2013[Article], 32734384, 8556303, 11101688, 9239681, 36604502, 34996830, 34782259) -
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CFTR-related disorder Pathogenic:1
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Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
The CFTR c.3200C>T; p.Ala1067Val variant (rs1800114; ClinVar Variation ID: 53683) is reported in the literature in individuals affected with congenital absence of vas deferens (CBAVD) or atypical cystic fibrosis, some of whom carry a pathogenic variant on the opposite chromosome (De Braekeleer 1996, Jezequel 1995, Welsh 2014). This variant is only found on three alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.936). Additionally, other amino acid substitutions at this codon (Thr, Pro, Asp) have been reported in individuals with CF or CFTR-related disorders (Ferec 1992, see link to CF mutation database). While the p.Ala1067Val variant is not predicted to cause classic cystic fibrosis, it is considered to be likely pathogenic for CFTR-related disorders. References: Link to cystic fibrosis mutation database: http://www.genet.sickkids.on.ca/cftr/Home.html De Braekeleer M and Ferec C. Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens. Mol Hum Reprod. 1996 Sep;2(9):669-77. PMID: 9239681. Ferec C et al. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nat Genet. 1992 Jun;1(3):188-91. PMID: 1284639. Jezequel P et al. Structural analysis of CFTR gene in congenital bilateral absence of vas deferens. Clin Chem. 1995 Jun;41(6 Pt 1):833-5. PMID: 7539342. Welsh SK et al. False-negative sweat chloride testing in a child with cystic fibrosis and undiagnosed hypohidrotic ectodermal dysplasia. Clin Pediatr (Phila). 2014 Oct;53(12):1203-5. PMID: 24419263. -
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Variant summary: CFTR c.3200C>T (p.Ala1067Val) 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 1.2e-05 in 250938 control chromosomes (gnomAD). c.3200C>T has been reported in the literature in the compound heterozygous state in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (e.g. Jezequel_1995, DeBraekeleer_1996, Woods_2013, Qu_2023). These data indicate that the variant is likely to be associated with disease. It was also reported as a non-informative genotype in a child with features of atypical CF and hypohydrotic ectodermal dysplasia (Welsh_2014). 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: 8556303, 9239681, 7539342, 11101688, 36604502, 25735457, 1284534, 24419263). ClinVar contains an entry for this variant (Variation ID: 53683). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at