Submissions for variant NM_024306.5(FA2H):c.94C>G (p.Arg32Gly)

gnomAD frequency: 0.00003  dbSNP: rs978032580

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474966	SCV000545825	uncertain significance	Spastic paraplegia	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 32 of the FA2H protein (p.Arg32Gly). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of FA2H-related conditions (PMID: 32624042; 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: 406878). 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 not expected to disrupt FA2H protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001117374	SCV001275551	uncertain significance	Hereditary spastic paraplegia 35	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848804	SCV002104694	uncertain significance	Hereditary spastic paraplegia	2020-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689744	SCV005185104	uncertain significance	not specified	2024-05-22	criteria provided, single submitter	clinical testing	Variant summary: FA2H c.94C>G (p.Arg32Gly) results in a non-conservative amino acid change located in the Cytochrome b5-like heme/steroid binding domain (IPR001199) of 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 2.9e-05 in 68276 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.94C>G has been reported in the literature in the compound heterozygous state in an individual affected with Neurodegeneration without significant white matter lesions or brain iron accumulation (Leal Ferman_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32624042). ClinVar contains an entry for this variant (Variation ID: 406878). Based on the evidence outlined above, the variant was classified as uncertain significance.