ClinVar

Description

Variant summary: CFTR c.3854C>T (p.Ala1285Val) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 0.00066 in 250862 control chromosomes (gnomAD), predominantly at a frequency of 0.0053 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is somewhat lower than the maximum expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence of the Vas Deferens (CBAVD) (0.013), allowing no conclusion about variant significance. c.3854C>T has been reported in the literature in at least two Asian Indian individuals affected with CBAVD, however no second (likely) pathogenic variant was specified in these cases (Sachdeva 2011, Gaikwad_2020). The variant was also found during carrier screening in homozygosity in an Asian Indian (Schwartz_2009) and an Australian individual (Archibald_2017), but no phenotype information was provided. These reports do not provide unequivocal conclusions about association of the variant with CBAVD. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance, one as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.