Submissions for variant NM_024306.5(FA2H):c.806G>A (p.Arg269His)

gnomAD frequency: 0.00001  dbSNP: rs1429546236

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219726	SCV001391678	pathogenic	Spastic paraplegia	2022-10-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg269 amino acid residue in FA2H. Other variant(s) that disrupt this residue have been observed in individuals with FA2H-related conditions (PMID: 29423566, 31130284), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 948467). This missense change has been observed in individual(s) with hereditary spastic paraplegia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 269 of the FA2H protein (p.Arg269His).
Centogene AG - the Rare Disease Company	RCV001250165	SCV001424410	likely pathogenic	Hereditary spastic paraplegia 35		criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001819910	SCV002064546	likely pathogenic	not provided	2020-01-29	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FA2H gene demonstrated a sequence change, c.806G>A, in exon 6 in the homozygous state that results in an amino acid change, p.Arg269His. The p.Arg269His change affects a highly conserved amino acid residue located in a domain of the FA2H protein that is known to be functional. The p.Arg269His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Mutation Taster, REVEL). This particular amino acid change does not appear to have been described in the literature in other patients with FA2H related disorders, however, a different sequence change, c.806G>T, affecting the same amino acid residue (p.Arg269Leu) has been described in a patient with spastic paraplegia in the compound heterozygous state (PMID: 24482476). Another sequence change, c.805C>T, affecting the same amino acid residue (p.Arg269Cys) has also been reported in a compound heterozygous state in patients with spastic paraplegia (PMIDs: 30564185, 29423566). This sequence change, c.806G>A, has been described in the gnomAD database with a low population frequency of 0.0011% (dbSNP rs1429546236); however it has not been observed in the homozygous state in any individuals. These collective evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001250165	SCV002571767	likely pathogenic	Hereditary spastic paraplegia 35	2024-12-26	criteria provided, single submitter	clinical testing	Variant summary: FA2H c.806G>A (p.Arg269His) results in a non-conservative amino acid change located in the Fatty acid hydroxylase domain (IPR006694) of 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 1.1e-05 in 177958 control chromosomes. c.806G>A has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia 35. including as a homozygous genotype or in at least one heterozygous individual without detected second variant with clinical features of Hereditary Spastic Paraplegia 35 (e.g. Marelli_2015, Cheema_2020, Labcorp (formerly Invitae), Krenn_2024). 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. The following publications have been ascertained in the context of this evaluation (PMID: 33083013, 38127101, 30713878). ClinVar contains an entry for this variant (Variation ID: 948467). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001250165	SCV004045937	likely pathogenic	Hereditary spastic paraplegia 35	2022-08-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001819910	SCV005440870	likely pathogenic	not provided	2024-06-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34852264, 31135052, 33083013, 30713878)