Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000795040 | SCV000934480 | likely pathogenic | Charcot-Marie-Tooth Neuropathy X; Combined oxidative phosphorylation deficiency | 2023-11-02 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 336 of the AIFM1 protein (p.Glu336Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of AIFM1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 641733). 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 AIFM1 protein function with a positive predictive value of 95%. 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. |
| Servicio Canario de Salud, |
RCV002468607 | SCV002765018 | uncertain significance | Charcot-Marie-Tooth disease X-linked recessive 4 | 2022-08-17 | criteria provided, single submitter | clinical testing | The c.1006G>A (p.Glu336Lys) AIFM1 variant has been reported in our laboratory in a 44-year-old male with diagnosis Charcot-Marie-Tooth Neuropathy and severe sensorineural hearing loss. Asymptomatic parents and sister. To our knowledge, this variant has never been reported in ABCC9 related-disorders patients. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 641733). In silico analysis (CADD, Mutation Taster, SIFT, PolyPhen2) supports that this missense variant has a deleterious effect on protein structure/function. To date there are no functional/experimental studies that evaluate the impact on protein. In summary, c.1006G>A (p.Glu336Lys) AIFM1 variant meets our criteria to be classified as Variant of Uncertain Significance-Probably Pathogenic based upon its absence from controls, computational evidence of pathogenicity and and the clinical correlation in this patient´s phenotype. |
| Gene |
RCV003329341 | SCV004036880 | uncertain significance | not provided | 2023-09-21 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |