Submissions for variant NM_000135.4(FANCA):c.1359+5G>C (rs183569738)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494125	SCV000582534	uncertain significance	not provided	2017-05-15	criteria provided, single submitter	clinical testing	The c.1359+5G>C variant in the FANCA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. In silico analysis predicts the natural splice donor site may be damaged. However, in the absence of RNA/functional studies, the actual effect of the c.1359+5G>C change in this individual is unknown. The c.1359+5G>C variant is observed in 5/10466 (0.05%) alleles from individuals of Latino background, in the ExAC dataset (Lek et al., 2016). We interpret c.1359+5G>C as a variant of uncertain significance.
Invitae	RCV001221856	SCV001393923	uncertain significance	Fanconi anemia	2019-05-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 of the FANCA gene. It does not directly change the encoded amino acid sequence of the FANCA protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs183569738, ExAC 0.05%). This variant has not been reported in the literature in individuals with FANCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 429863). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.