FANCA c.3624C>T (p.Ser1208=) is a hypomorphic splice variant associated with delayed onset of Fanconi anemia.

Fanconi anemia (FA) is a hereditary, DNA repair deficiency disorder caused by pathogenic variants in any one of the 22 known genes (FANCA-FANCW). Variants in FANCA account for nearly two-thirds of all FA patients. Clinical presentation of FA can be heterogeneous and include congenital abnormalities, progressive bone marrow failure, and predisposition to cancer. Here we describe a relatively mild disease manifestation among six individuals diagnosed with FA, each compound heterozygous for one established pathogenic FANCA variant and one FANCA exon 36 variant, c.3624C>T. These individuals had delayed onset of hematological abnormalities, increased survival, reduced incidence of cancer, and improved fertility. Though predicted to encode a synonymous change (p.Ser1208=), the c.3624C>T variant causes a splicing error resulting in a FANCA transcript missing the last 4 bp of exon 36. Deep sequencing and quantitative RT-PCR analysis revealed that 6-10% of the FANCA transcripts included the canonical splice product, which generated wild-type FANCA protein. Consistently, functional analysis of cell lines from the studied individuals revealed presence of residual FANCD2 ubiquitination and FANCD2 foci formation, better cell survival, and decreased late S/G2 accumulation in response to DNA interstrand crosslinking agent, indicating presence of residual activity of the FA repair pathway. Thus, the c.3624C>T variant is a hypomorphic allele, which contributes to delayed manifestation of FA disease phenotypes in individuals with at least one c.3624C>T allele.