ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3200C>T (p.Ala1067Val) (rs1800114)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000586398 SCV000339600 uncertain significance not provided 2016-02-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175335 SCV000696957 uncertain significance not specified 2021-02-27 criteria provided, single submitter clinical testing 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. c.3200C>T has been reported in the literature in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (example, DeBraekeleer_1996, Jezequel_1995, Woods_2013). These data indicate that the variant may 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). At-least one report of a co-occurrence in cis with another pathogenic variant in individuals with CBAVD has been reported (De Braekeleer_1996, CFTR c.1521_1523delCTT, p.F508del), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic, n=1, VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000670817 SCV000795720 uncertain significance Cystic fibrosis 2017-11-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000586398 SCV000883571 likely pathogenic not provided 2017-06-20 criteria provided, single submitter clinical testing The CFTR c.3200C>T; p.Ala1067Val variant (rs1800114) has been reported in an individual with congenital absence of vas deferens (CBAVD), who carries the severe pathogenic F508del on the other chromosome (Jezequel 1995). Additionally, a different variant at this codon, p.Ala1067Pro, has been reported in an individual with CBAVD who also carries F508del (see database link), and a p.Ala1067Thr change has been reported in a cystic fibrosis (CF) patient with pancreatic insufficiency who also carries F508del (Ferec 1992). The p.Ala1067Thr variant was shown by functional analysis to have reduced CFTR maturation and chloride transport activity compared to wild type protein (Van Goor 2014). A fourth variant at this codon, p.Ala1067Asp, was found homozygously in a CF patient with mild pulmonary disease, and pancreatic insufficiency (see database link). The p.Ala1067Val variant is reported in ClinVar (Variation ID: 53683), and observed in general population databases at frequencies of 0.008 percent (1/13006 alleles, Exome Variant Server), and 0.001 percent (3/245722 alleles, Genome Aggregation Database). The alanine at codon 1067 is highly conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Based on the above information, this variant is suspected to be mildly pathogenic. REFERENCES: Link to ClinVar database for p.Ala1067Val: https://www.ncbi.nlm.nih.gov/clinvar/variation/53683/ Link to SickKids database for p.Ala1067Pro: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1631 Link to SickKids database for p.Ala1067Asp: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1200 Ferec C et al. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nat Genet. 1992 Jun;1(3):188-91. 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. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36.
Invitae RCV000670817 SCV001576971 likely pathogenic Cystic fibrosis 2020-08-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1067 of the CFTR protein (p.Ala1067Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs1800114, ExAC 0.003%). This variant has been reported with a pathogenic variant in CFTR in individuals affected with congenital bilateral absence of the vas deferens (PMID: 7539342, 8556303, Invitae). It has also been reported in an individual with cystic fibrosis (PMID: 7689902), although in that individual a second variant was not specified. ClinVar contains an entry for this variant (Variation ID: 53683). 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 C1). The p.Ala1067 amino acid residue in CFTR has been determined to be clinically significant (PMID: 1284639, 23891399, 8702904, 8662892, 27131402). This suggests that variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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