Submissions for variant NM_024306.5(FA2H):c.159_176del (p.Arg53_Ile58del)

dbSNP: rs759947457

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002293414	SCV002586485	pathogenic	not provided	2025-01-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect suggesting loss of function (PMID: 20104589); In-frame deletion of 6 amino acids in a non-repeat region; In silico analysis supports 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: 31130284, 37152446, 20104589, 33246395, 24359114, 38275596, 36109173, 38306901, 36002593, 37510308, 39304850)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513206	SCV003260346	pathogenic	Spastic paraplegia	2024-10-24	criteria provided, single submitter	clinical testing	This variant, c.159_176del, results in the deletion of 6 amino acid(s) of the FA2H protein (p.Arg53_Ile58del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759947457, gnomAD 0.01%). This variant has been observed in individuals with clinical features of FA2H-related conditions and/or hereditary spastic paraplegia (PMID: 20104589, 31130284, 33246395; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30871). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FA2H function (PMID: 20104589). For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV000023856	SCV004013876	pathogenic	Hereditary spastic paraplegia 35		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Inframe deletion located in a nonrepeat region is predicted to change the length of the protein and disrupt normal protein function. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20104589). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 31130284, 33246395). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the the same family or the similarly affected unrelated family (PMID: 31130284, 33246395). The variant has been reported to be associated with FA2H-related disorder (ClinVar ID: VCV000030871 / PMID: 20104589). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Centre For Genomic Medicine, NCGM	RCV000023856	SCV005382297	pathogenic	Hereditary spastic paraplegia 35	2023-05-20	criteria provided, single submitter	clinical testing	The observed inframe deletion c.159_176del(p.Arg53_Ile58del) variant has been reported previously in homozygous state in patients affected with spastic paraplegia (Abbas S, et. al., 2021). Functional studies demonstrate a damaging effect suggesting loss of function (Dick et al., 2010). This variant is present with an allele frequency of 0.002% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). It has also been observed to segregate with disease in related individuals (Abbas S, et. al., 2021). This p.Arg53_Ile58del causes deletion of amino acid Arginine at position 53 to Isoleucine at position 58. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000023856	SCV000045147	pathogenic	Hereditary spastic paraplegia 35	2010-04-01	no assertion criteria provided	literature only
Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology	RCV000023856	SCV004812220	pathogenic	Hereditary spastic paraplegia 35	2023-11-02	no assertion criteria provided	research