Submissions for variant NM_001371596.2(MFSD8):c.1393C>T (p.Arg465Trp)

dbSNP: rs1043984708

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001050490	SCV001214599	uncertain significance	Neuronal ceroid lipofuscinosis 7	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 465 of the MFSD8 protein (p.Arg465Trp). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with variant late-infantile neuronal ceroid lipofuscinosis (PMID: 19201763). ClinVar contains an entry for this variant (Variation ID: 847034). 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 MFSD8 protein function. Experimental studies have shown that this missense change does not substantially affect MFSD8 function (PMID: 22668694). This variant disrupts the p.Arg465 amino acid residue in MFSD8. Other variant(s) that disrupt this residue have been observed in individuals with MFSD8-related conditions (PMID: 21990111), which suggests that this may be a clinically significant amino acid residue. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469331	SCV002766542	likely pathogenic	Neuronal ceroid lipofuscinosis	2022-11-15	criteria provided, single submitter	clinical testing	Variant summary: MFSD8 c.1393C>T (p.Arg465Trp) results in a non-conservative amino acid change in 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 8e-06 in 251156 control chromosomes (gnomAD). c.1393C>T has been reported in the literature in a homozygous individual affected with late-infantile neuronal ceroid lipofuscinosis (Kousi_2009). These data indicate that the variant may be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and analysis of neural precursors cells (NPCs) generated from induced pluripotent cells (iPCs) derived from the patient homozygous for the missense variant showed accumulation of structurally impaired mitochondria and elevated mitochondrial reactive oxygen species (mROS) levels (Lopez-Fabuel_2022). In addition, although additional experiments demonstrated no detrimental effect on proteolytic cleavage of the variant MFSD8 protein (Steenhuis_2012), however the variant resulted in significantly reduced lysosomal Cl- currents (Wang_2021). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Illumina Laboratory Services, Illumina	RCV001050490	SCV004014716	likely pathogenic	Neuronal ceroid lipofuscinosis 7	2023-02-21	criteria provided, single submitter	clinical testing	The MFSD8 c.1393C>T (p.Arg465Trp) missense variant results in a substitution of an arginine at amino acid position 465 with tryptophan. This variant has been reported in a homozygous state in a 4.5 year old boy of Albanian/Greek ancestry with late-infantile onset neuronal ceroid lipofuscinoses (PMID: 19201763). A different variant at the same amino acid position, c.1394G>A (p.Arg465Gln), was reported in a compound heterozygous state with an established pathogenic splice variant in an affected individual of Turkish descent (PMID: 21990111). The c.1393C>T variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000008 in the total population (version 2.1.1). Using whole-endolysosomal patch-clamp recording, Wang et al. 2021 demonstrated that HEK293 cells overexpressing MFSD8 cDNA constructs harboring the c.1393C>T variant produced significantly reduced chloride currents compare to wild type (PMID: 34910516). At a cellular level, patient derived neural precursor cells, homozygous for c.1393C>T show an increase in mitochondrial reactive oxygen species, lysosomal accumulation of mitochondria and mitochondrial condensation in perinuclear region of the cell (PMID: 35087090). Based on the available evidence, the c.1393C>T (p.Arg465Trp) variant is classified as likely pathogenic for neuronal ceroid lipofuscinoses.