Description
Variant summary: CFTR c.2846A>T (p.His949Leu) 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 8e-06 in 251382 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2846A>T has been reported in the literature in at least one individual with atypical CF and equivocal sweat chloride levels (e.g., McGinniss_2005). It has also been reported as a complex allele in cis with p.H949L and another disease causing CF variant in trans (i.e., compound heterozygous genotype) in patients with CF (at least four ascertainments) and CFTR-RD (at least one ascertainment) (e.g., Polizzi_2011, Diana_2016, Paganin_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis in isolation. 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: 16189704, 21931512, 26911355, 25898134). ClinVar contains an entry for this variant (Variation ID: 53578). Based on the evidence outlined above, the variant was classified as uncertain significance.
# | Sample | Method | Observation |
---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
---|
1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |