ClinVar Miner

Submissions for variant NM_001371596.2(MFSD8):c.863C>T (p.Thr288Ile)

gnomAD frequency: 0.00001  dbSNP: rs755384900
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188175 SCV000241782 uncertain significance not provided 2013-02-22 criteria provided, single submitter clinical testing p.Thr288Ile (ACC>ATC): c.863 C>T in exon 9 of the MFSD8 gene (NM_152778.2)The Thr288Ile missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Thr288Ile in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a polar Threonine residue is replaced by a non-polar Isoleucine residue. Thr288Ile alters a conserved position in the extracellular loop between the seventh and eighth transmembrane domains of the protein and another missense mutation (Thr294Lys) in this region has been reported in association with late-infantile neuronal ceroid lipofuscinoses (vLINCL) (Kousi et al., 2009; Aiello et al., 2009). In addition, multiple in-silico algorithms predict Thr288Ile is damaging to the structure/function of the protein. Based on the currently available information, it is unclear whether Thr288Ile is a disease-causing mutation or a rare benign variant.The variant is found in CHILD-EPI panel(s).
Fulgent Genetics, Fulgent Genetics RCV000764533 SCV000895618 uncertain significance Neuronal ceroid lipofuscinosis 7; Macular dystrophy with central cone involvement 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV002517000 SCV003271200 uncertain significance Neuronal ceroid lipofuscinosis 7 2022-08-03 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 288 of the MFSD8 protein (p.Thr288Ile). This variant is present in population databases (rs755384900, gnomAD 0.003%). 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: 206156). 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 C15"). 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.
Ambry Genetics RCV002517001 SCV003555393 uncertain significance Inborn genetic diseases 2022-02-15 criteria provided, single submitter clinical testing Occurs in the last base pair of the exon Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV001828004 SCV002084784 uncertain significance Late-infantile neuronal ceroid lipofuscinosis 2020-08-18 no assertion criteria provided clinical testing

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