ClinVar Miner

Submissions for variant NM_001018115.3(FANCD2):c.1948-6C>A

gnomAD frequency: 0.00001  dbSNP: rs779350241
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001531561 SCV001746755 likely pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282477 SCV002570976 pathogenic Fanconi anemia 2022-07-21 criteria provided, single submitter clinical testing Variant summary: FANCD2 c.1948-6C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3 acceptor site and one predicts the variant abolishes a 3 acceptor site. Experimental evidence supports these predictions demonstrating that this variant affects mRNA splicing, leading to exon 22 skipping (Kalb_2007). The variant allele was found at a frequency of 1.2e-05 in 251134 control chromosomes (gnomAD). c.1948-6C>A has been reported in the literature in multiple compound heterozygous individuals affected with Fanconi Anemia, including two siblings (Kalb_2007). These data indicate that the variant is likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001531561 SCV003923760 pathogenic not provided 2024-03-25 criteria provided, single submitter clinical testing Non-canonical splice site variant demonstrated to result in loss of function (PMID: 17436244); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17436244)
Leiden Open Variation Database RCV001194921 SCV001364786 pathogenic Fanconi anemia complementation group D2 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.

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