Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001053491 | SCV001217757 | uncertain significance | Fanconi anemia | 2022-07-18 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1463 of the FANCD2 protein (p.Leu1463Pro). This variant is present in population databases (rs767893462, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FANCD2-related conditions. This missense change has been observed to co-occur in individuals with a different variant in FANCD2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 849509). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. |
Genetic Services Laboratory, |
RCV001819775 | SCV002066648 | uncertain significance | not specified | 2020-11-02 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the FANCD2 gene demonstrated a sequence change, c.4388T>C, in exon 43 that results in an amino acid change, p.Leu1463Pro. This sequence change does not appear to have been previously described in patients with FANCD2-related disorders and has been described in the gnomAD database with a low population frequency of 0.0036% (dbSNP rs767893462). The p.Leu1463Pro change affects a poorly conserved amino acid residue located in a domain of the FANCD2 protein that is not known to be functional. The p.Leu1463Pro substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Leu1463Pro change remains unknown at this time. |
Sema4, |
RCV001053491 | SCV002529533 | uncertain significance | Fanconi anemia | 2021-09-13 | criteria provided, single submitter | curation | |
Fulgent Genetics, |
RCV002489629 | SCV002789000 | uncertain significance | Fanconi anemia complementation group D2 | 2022-04-21 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV003243442 | SCV003951028 | uncertain significance | Inborn genetic diseases | 2023-03-16 | criteria provided, single submitter | clinical testing | The c.4388T>C (p.L1463P) alteration is located in exon 43 (coding exon 42) of the FANCD2 gene. This alteration results from a T to C substitution at nucleotide position 4388, causing the leucine (L) at amino acid position 1463 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |