Submissions for variant NM_024306.5(FA2H):c.703C>T (p.Arg235Cys)

gnomAD frequency: 0.00001  dbSNP: rs387907039

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797590	SCV002041771	uncertain significance	not specified	2021-11-07	criteria provided, single submitter	clinical testing	Variant summary: FA2H c.703C>T (p.Arg235Cys) 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 4e-06 in 251222 control chromosomes. c.703C>T has been reported in the literature as a homozygous genotype in one individual affected with autosomal recessive form of HSP (SPG35) (example, Dick_2010). These data indicate that the variant may be associated with disease. However, a subsequent study has reported that cerebral iron accumulation is not a major feature of FA2H associated autosomal recessive spastic paraplegia (SPG35) (Marelli_2015). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Neurodegeneration with brain iron accumulation. At least one publication reports experimental evidence evaluating an impact on protein function (Dick_2010). The most pronounced variant effect results in >50%-90% of normal levels of hydroxylated ceramides. One clinical diagnostic laboratory (most likely the originator of the reported individual, Dick_2010) has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV002509169	SCV002818890	pathogenic	not provided	2023-01-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a reduction in 2-hydroxylated ceramide activity (Dick et al., 2010); 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: 26944241, 33144682, 20104589)
Revvity Omics, Revvity	RCV000023855	SCV003831176	likely pathogenic	Hereditary spastic paraplegia 35	2022-12-14	criteria provided, single submitter	clinical testing
OMIM	RCV000023855	SCV000045146	pathogenic	Hereditary spastic paraplegia 35	2010-04-01	no assertion criteria provided	literature only
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000023855	SCV000891500	uncertain significance	Hereditary spastic paraplegia 35	2017-12-30	no assertion criteria provided	curation