Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV001195534 | SCV001365912 | likely pathogenic | Hereditary spastic paraplegia | 2019-12-04 | criteria provided, single submitter | clinical testing | The p.Thr207Met variant in FA2H has been reported in the compound heterozygous state in 4 individuals with spastic paraplegia and segregated with disease in 2 affected individuals from 2 families (Pensato 2014, Kara 2016, Magariello 2017, Rattay 2019). It has also been identified in 0.002% (4/249728) of pan ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive spastic paraplegia. ACMG/AMP Criteria applied: PM3_Moderate, PM2, PP1_Moderate, BP4. |
| Labcorp Genetics |
RCV001859178 | SCV002233684 | pathogenic | Spastic paraplegia | 2024-01-09 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 207 of the FA2H protein (p.Thr207Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 24833714, 27217339, 28017243, 31135052). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 930104). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FA2H protein function. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001542494 | SCV003923177 | likely pathogenic | Hereditary spastic paraplegia 35 | 2023-03-02 | criteria provided, single submitter | clinical testing | Variant summary: FA2H c.620C>T (p.Thr207Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249728 control chromosomes. c.620C>T has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia 35, however in some cases the patient's second variant was unknown significance (HSP/SPG35) (Pensato_2014, Kara_2016, Magariello_2017, Chen_FA2H_BMCN_2022, etc.). The variant was reported to segregate in at least 2 individuals from 2 families (Magariello_2017, Pensato_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Genomics England Pilot Project, |
RCV001542494 | SCV001760381 | likely pathogenic | Hereditary spastic paraplegia 35 | no assertion criteria provided | clinical testing |