Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000483483 | SCV000567492 | uncertain significance | not provided | 2022-11-17 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29376581, 34758253, 24299421, 20853438, 29423566, 25141825, 31589614, 32907636, 34852264, 31837835, 27217339, 31135052) |
| Genomic Research Center, |
RCV000023857 | SCV001251783 | pathogenic | Hereditary spastic paraplegia 35 | 2020-05-03 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002513207 | SCV003266316 | pathogenic | Spastic paraplegia | 2022-07-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 154 of the FA2H protein (p.Arg154Cys). This variant is present in population databases (rs387907040, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of FA2H-related conditions (PMID: 20853438, 27217339, 31135052, 32907636). ClinVar contains an entry for this variant (Variation ID: 30872). 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. Studies have shown that this missense change alters FA2H gene expression (PMID: 20853438). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317044 | SCV004021201 | pathogenic | Neurodegeneration with brain iron accumulation | 2023-06-16 | criteria provided, single submitter | clinical testing | Variant summary: FA2H c.460C>T (p.Arg154Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251280 control chromosomes. c.460C>T has been reported in the literature in multiple individuals affected with FA2H-related conditions (e.g., Kruer_2010, Rattay_2019, Tsang_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence demonstrating reduced levels of protein expression in mutant cells, indicating reduced stability of the mRNA or protein product (Kruer_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20853438, 31135052, 32907636). Three ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as a variant on uncertain significance, while two submitter classified it as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV000023857 | SCV000045148 | pathogenic | Hereditary spastic paraplegia 35 | 2010-11-01 | no assertion criteria provided | literature only | |
| Genomics England Pilot Project, |
RCV000023857 | SCV001760382 | likely pathogenic | Hereditary spastic paraplegia 35 | no assertion criteria provided | clinical testing |