Submissions for variant NM_001371596.2(MFSD8):c.154G>A (p.Gly52Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002308650	SCV002600679	uncertain significance	not specified	2022-10-22	criteria provided, single submitter	clinical testing	Variant summary: MFSD8 c.154G>A (p.Gly52Arg) 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 1.6e-05 in 250298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.154G>A has been reported in the literature as a presumed biallelic genotype in at-least one individual affected with features of Variant-Late Infantile Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Aiello_2009). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003099117	SCV003525867	uncertain significance	Neuronal ceroid lipofuscinosis 7	2021-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 52 of the MFSD8 protein (p.Gly52Arg). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs779838200, gnomAD 0.004%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 19177532). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.