Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000792843 | SCV000932167 | uncertain significance | Fanconi anemia | 2022-09-06 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 697 of the FANCA protein (p.Val697Ile). This variant is present in population databases (rs376888740, gnomAD 0.006%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 29098742). ClinVar contains an entry for this variant (Variation ID: 639926). 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 not expected to disrupt FANCA protein function. Experimental studies have shown that this missense change does not substantially affect FANCA function (PMID: 29098742). 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. |
| Fulgent Genetics, |
RCV002487646 | SCV002789125 | uncertain significance | Fanconi anemia complementation group A | 2022-05-09 | criteria provided, single submitter | clinical testing | |
| St. |
RCV002487646 | SCV003928110 | uncertain significance | Fanconi anemia complementation group A | 2023-04-18 | criteria provided, single submitter | clinical testing | The FANCA c.2089G>A (p.Val697Ile) change has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, and functional analysis indicated that the variant is non-pathogenic (PMID: 29098742). This variant was reportedly observed in one individual with Fanconi anemia, however the zygosity or identification of a second variant was not indicated (PMID: 29098742). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
| Gene |
RCV003233850 | SCV003931010 | uncertain significance | not provided | 2022-11-28 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with Fanconi anemia, however, functional assays revealed that this variant leads to protein expression similar to wild type and may not be pathogenic (Kimble et al., 2018); This variant is associated with the following publications: (PMID: 29098742) |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003233850 | SCV004221946 | uncertain significance | not provided | 2023-01-26 | criteria provided, single submitter | clinical testing | In the published literature, this variant has been reported in at least one individual with Fanconi anemia (PMID: 29098742 (2018)). Functional studies have shown that this variant has no deleterious effect on FANCA protein expression, nuclear localization, and cell survival (PMID: 29098742 (2018)). The frequency of this variant in the general population, 0.000062 (8/129198 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. |
| Natera, |
RCV000792843 | SCV002092641 | uncertain significance | Fanconi anemia | 2020-03-21 | no assertion criteria provided | clinical testing |