ClinVar Miner

Submissions for variant NM_001371596.2(MFSD8):c.1408A>G (p.Met470Val)

dbSNP: rs764549054
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188184 SCV000241791 uncertain significance not provided 2018-10-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MFSD8 gene. The M470V variant has been previously reported in an individual with NCL; however, a second MFSD8 variant was not identified (Kousi et al., 2012). The M470V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The M470V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000693756 SCV000821637 uncertain significance Neuronal ceroid lipofuscinosis 7 2022-06-27 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 470 of the MFSD8 protein (p.Met470Val). This variant is present in population databases (rs764549054, gnomAD 0.003%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinoses (PMID: 21990111). ClinVar contains an entry for this variant (Variation ID: 206164). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Pars Genome Lab RCV000693756 SCV001736838 uncertain significance Neuronal ceroid lipofuscinosis 7 2021-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002228826 SCV002511975 uncertain significance not specified 2022-04-01 criteria provided, single submitter clinical testing Variant summary: MFSD8 c.1408A>G (p.Met470Val) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 260808 control chromosomes (gnomAD and publication). This frequency is not higher than expected for a pathogenic variant in MFSD8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (8.8e-05 vs 0.00094), allowing no conclusion about variant significance. c.1408A>G has been reported in the literature in a heterozygous individual without another variant identified who was affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Kousi_2012), but it has also been reported in a homozygous individual who lacked Batten Disease phenotype (Abouelhoda_2016). These reports do not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breakthrough Genomics, Breakthrough Genomics RCV000188184 SCV005190277 uncertain significance not provided criteria provided, single submitter not provided
Natera, Inc. RCV001833124 SCV002084752 uncertain significance Late-infantile neuronal ceroid lipofuscinosis 2020-02-28 no assertion criteria provided clinical testing

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