ClinVar

Description

Variant summary: The CFTR c.2735C>T (p.Ser912Leu) variant involves the alteration of a not conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 279/304800 control chromosomes, predominantly observed in the Ashkenazi Jewish subpopulation in gnomAD at a frequency of 0.017041 (173/10152). This frequency is about 1.3 times the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. However, it needs to be noted that this observation needs to take into account the nature of this population having lower genetic heterogeneity. This variant has been reported in multiple affected individuals; however, many of the reported cases also carried p.G1244V in cis or in cis with another potentially pathogenic variant. Functional data shows that the variant of interest, alone, acts comparable to wild type function, however, in cis with another potentially pathogenic variant such as G1244V (shown to have pathogenic properties, in isolation) drastically affects functionality (Clain_2005). In addition, an asymptomatic male was compound heterozygous (in trans) for this variant and a pathogenic (p.R709X) was reported (Clain_2005), supporting for benign outcome. Furthermore, multiple clinical diagnostic laboratories/reputable databases and publications (Clain_2005 and Zietkiewicz_2014) cite the variant of interest in isolation as Benign. Therefore, taken all together, variant of interest in isolation is classified as benign, however, one must take into consideration when the variant of interest is in a complex allele with another potentially pathogenic CFTR variant (in cis), the variant of interest may act as a modifier of pathogenicity.