Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Athena Diagnostics Inc | RCV000056856 | SCV001144051 | uncertain significance | not provided | 2019-03-15 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000056856 | SCV001785076 | likely pathogenic | not provided | 2021-06-08 | criteria provided, single submitter | clinical testing | Identified in an adult patient with bulbar and/or pseudobulbar signs, ataxia, and brainstem abnormalities, contrast enhancement, and spinal cord abnormalities noted on MRI in the published literature; the variant was absent in the mother however the father was not tested (Caroli et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17894839, 27535533, 20301351, 18684770, 29421207, 26478912, 23430549) |
Invitae | RCV000056856 | SCV002187088 | uncertain significance | not provided | 2021-12-03 | criteria provided, single submitter | clinical testing | This missense change has been observed in at least one individual who was not affected with GFAP-related conditions (Invitae). This missense change has been observed in individual(s) with Alexander disease (PMID: 17894839). This variant is present in population databases (rs267607510, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 70 of the GFAP protein (p.Arg70Gln). ClinVar contains an entry for this variant (Variation ID: 66461). 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. This variant disrupts the p.Arg70 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16240361, 17438228, 17894839, 20849398). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). |
Concord Molecular Medicine Laboratory, |
RCV000192099 | SCV003035514 | likely pathogenic | Alexander disease | 2023-01-24 | criteria provided, single submitter | clinical testing | This missense change is one of the common variants causing the adult form of Alexander Disease (PMID: 20301351, 17894839, 18684770, 18495313, 18388212, 24306001). Disease onset is typically in the third decade in described cases with the same variant (PMID: 36088400). This variant is observed in a patient with adult-onset spastic quadriparesis. MRI showed atrophic medulla with narrowed cervical cord. This variant is present in a heterozygous state at a very low frequency in control population (gnomAD). It is located in a mutational hotspot and within the functional IF rod domain in the special “head” region. Another amino acid change in the same codon has been reported as disease causing (ClinVar ID: 66460). In silico analysis by REVEL predicts the effect of the variant as uncertain (REVEL:0.607), MetaRNN as pathogenic (0.953). The current evidence available allows a classification of the variant as “likely pathogenic” (ACMG criteria: PM1, PM5, PS4_moderate, PM2_supporting). |
Epithelial Biology; Institute of Medical Biology, |
RCV000056856 | SCV000087969 | not provided | not provided | no assertion provided | not provided | ||
Gene |
RCV000192099 | SCV000222953 | not provided | Alexander disease | no assertion provided | literature only |