Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001265744 | SCV001443913 | pathogenic | Inborn genetic diseases | 2019-02-04 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002512995 | SCV003448545 | likely pathogenic | Fanconi anemia | 2023-09-14 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1236 of the FANCD2 protein (p.Arg1236His). This variant is present in population databases (rs121917786, gnomAD 0.003%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 11239453, 17436244). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12038). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FANCD2 protein function. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 17436244). 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. |
| Baylor Genetics | RCV000012818 | SCV004196725 | likely pathogenic | Fanconi anemia complementation group D2 | 2023-09-26 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002512995 | SCV005380424 | pathogenic | Fanconi anemia | 2024-08-22 | criteria provided, single submitter | clinical testing | Variant summary: FANCD2 c.3707G>A (p.Arg1236His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251190 control chromosomes. c.3707G>A has been reported in the literature in the presumed compound heterozygous or compound heterozygous state in multiple individuals affected with Fanconi Anemia (example, Timmers_2001, Kalb_2007, Chang_2023), including 2 individuals carrying a pathogenic variant in trans. This variant also segregated with disease in at least 1 family (example, Timmers_2001). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete absence of FANCD2 protein in patient-derived cells (example, Timmers_2001). It has been suggested that this variant may also result in a splicing defect, however no data were shown (example, Kalb_2007). The following publications have been ascertained in the context of this evaluation (PMID: 36463940, 17436244, 11239453). ClinVar contains an entry for this variant (Variation ID: 12038). Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV000012818 | SCV000033058 | pathogenic | Fanconi anemia complementation group D2 | 2001-02-01 | no assertion criteria provided | literature only | |
| Leiden Open Variation Database | RCV000012818 | SCV001364797 | pathogenic | Fanconi anemia complementation group D2 | 2020-02-28 | no assertion criteria provided | curation | Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. |