Submissions for variant NM_001371596.2(MFSD8):c.350C>G (p.Ala117Gly)

gnomAD frequency: 0.00001  dbSNP: rs759795397

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188165	SCV000241772	uncertain significance	not provided	2014-09-16	criteria provided, single submitter	clinical testing	p.Ala117Gly (GCC>GGC): c.350 C>G in exon 5 of the MFSD8 gene (NM_152778.2)A variant of unknown significance has been identified in the MFSD8 gene. The c.350 C>G 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. Multiple in-silico splice prediction models predict that c.350 C>G creates a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.350 C>G does not alter splicing, it will result in the A117G missense substitution. The A117G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to 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 INFANT-EPI panel(s).
Ambry Genetics	RCV002336498	SCV002618875	uncertain significance	Inborn genetic diseases	2018-09-15	criteria provided, single submitter	clinical testing	The p.A117G variant (also known as c.350C>G), located in coding exon 4 of the MFSD8 gene, results from a C to G substitution at nucleotide position 350. The alanine at codon 117 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516998	SCV003478828	uncertain significance	Neuronal ceroid lipofuscinosis 7	2022-06-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 117 of the MFSD8 protein (p.Ala117Gly). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 206148). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.