ClinVar Genomic variation as it relates to human health

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This sequence change affects a donor splice site in intron 27 of the FANCD2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCD2 are known to be pathogenic (PMID: 17436244). This variant is present in population databases (rs142365855, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 26633542, 34327028). ClinVar contains an entry for this variant (Variation ID: 265138). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Observed in homozygous state in a male patient with ambiguous genitalia, iron deficiency anemia, and failure to thrive, with no other features of Fanconi anemia (PMID: 34327028); Previously reported in an individual with growth failure; however, additional clinical and segregation data were not provided (PMID: 26633542); This variant is associated with the following publications: (PMID: 34327028, 26633542)

Variant summary: FANCD2 c.2605+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of FANCD2 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250564 control chromosomes. c.2605+1G>A has been reported in the literature in individuals affected with features of Fanconi Anemia, including at least one homozygote (e.g., Retterer_2016, AlJabri_2021, Kunisetty_2024). These data indicate that the variant may be associated with disease. 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: 34327028, 38502138, 26633542). ClinVar contains an entry for this variant (Variation ID: 265138). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The VHL c.-68866G>A variant is located in the 5' untranslated region. This variant was reported in an individual with growth abnormality, although no additional clinical or genetic information was provided (Retterer et al. 2016. PubMed ID: 26633542). This variant was also described in the homozygous state in an individual with iron deficiency anemia and ambiguous genitalia (Al Jabri et al. 2021. PubMed ID: 34327028). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in FANCD2 are expected to be pathogenic. This variant is interpreted as likely pathogenic.