Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000555976 | SCV000629519 | pathogenic | Spastic paraplegia | 2023-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 44 of the FA2H protein (p.Pro44Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive FA2H-related conditions and/or hereditary spastic paraplegia (PMID: 27316240, 33059505; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 458305). 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 FA2H protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002265790 | SCV002547566 | likely pathogenic | Neurodegeneration with brain iron accumulation | 2022-05-13 | criteria provided, single submitter | clinical testing | Variant summary: FA2H c.131C>A (p.Pro44Gln) results in a non-conservative amino acid change located in the Cytochrome b5-like heme/steroid binding domain (IPR001199) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 109458 control chromosomes. c.131C>A has been reported in the literature as a homozygous genotype and as an unmasked recessive genotype due to paternal UPD16 in at-least two individuals affected with spastic paraplegia type 35 (SPG35) (example, Soehn_2016 cited by Rattay_2019, Carrasco_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping but not all inclusive evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. |