ClinVar Miner

Submissions for variant NM_152778.3(MFSD8):c.1361T>C (p.Met454Thr) (rs559155109)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480079 SCV000565132 uncertain significance not provided 2018-07-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MFSD8 gene. The M454T variant has been reported previously in families with retinal disease and NCL who were homozygous for this change (Patiño et al., 2014; Khan et al., 2017). Family members who were heterozygous for this variant were reportedly unaffected. The M454T variant is observed in 26/30726 (0.08%) alleles from individuals of South Asian background, including 1 homozygous individual in large population cohorts (Lek et al., 2016). The M454T 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. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics RCV000717023 SCV000847868 uncertain significance Seizures 2016-09-20 criteria provided, single submitter clinical testing The p.M454T variant (also known as c.1361T>C), located in coding exon 12 of the MFSD8 gene, results from a T to C substitution at nucleotide position 1361. The methionine at codon 454 is replaced by threonine, an amino acid with similar properties. This variant, in cis with a second alteration (c.1219T>C, p.W407R), has been reported in the homozygous state in siblings with late-infantile neuronal ceroid lipofuscinosis identified by exome sequencing; it is not known which of the two alterations is disease causing or if there is a synergistic effect (Patiño LC et al. PLoS ONE, 2014 Oct;9:e109576). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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.
Invitae RCV000805545 SCV000945503 pathogenic Neuronal ceroid lipofuscinosis 7 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 454 of the MFSD8 protein (p.Met454Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs559155109, ExAC 0.08%). This variant has been observed to segregate with neuronal ceroid lipofuscinosis in a family (PMID: 25333361) and in several unrelated individuals affected with retinal dystrophy (PMID: 28586915, 28041643). ClinVar contains an entry for this variant (Variation ID: 418295). 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). For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504782 SCV000598755 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505013 SCV000598756 likely pathogenic Stargardt disease 1 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505174 SCV000598757 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
Genomics England Pilot Project,Genomics England RCV001542748 SCV001760131 likely pathogenic Macular dystrophy with central cone involvement no assertion criteria provided clinical testing

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