Submissions for variant NM_001371596.2(MFSD8):c.1174G>A (p.Glu392Lys)

gnomAD frequency: 0.00004  dbSNP: rs773610115

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188193	SCV000241800	uncertain significance	not provided	2014-10-27	criteria provided, single submitter	clinical testing	p.Glu392Lys (GAA>AAA): c.1174 G>A in exon 12 of the MFSD8 gene (NM_152778.2). A variant of unknown significance has been identified in the MFSD8 gene. The E392K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E392K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Neuberg Centre For Genomic Medicine, NCGM	RCV002510566	SCV002820161	uncertain significance	Neuronal ceroid lipofuscinosis 7		criteria provided, single submitter	clinical testing	The missense variant c.1174G>A (p.Glu392Lys) in MFSD8 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu392Lys variant is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid Glu at position 392 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu392Lys in MFSD8 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance
Labcorp Genetics (formerly Invitae), Labcorp	RCV002510566	SCV003518841	uncertain significance	Neuronal ceroid lipofuscinosis 7	2022-05-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 392 of the MFSD8 protein (p.Glu392Lys). This variant is present in population databases (rs773610115, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MFSD8-related conditions. ClinVar contains an entry for this variant (Variation ID: 206173). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV004639168	SCV005130681	uncertain significance	Inborn genetic diseases	2024-03-15	criteria provided, single submitter	clinical testing	The c.1174G>A (p.E392K) alteration is located in exon 12 (coding exon 11) of the MFSD8 gene. This alteration results from a G to A substitution at nucleotide position 1174, causing the glutamic acid (E) at amino acid position 392 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001828007	SCV002084763	uncertain significance	Late-infantile neuronal ceroid lipofuscinosis	2019-11-11	no assertion criteria provided	clinical testing