ClinVar Miner

Submissions for variant NM_001371596.2(MFSD8):c.1262C>T (p.Thr421Ile)

gnomAD frequency: 0.00001  dbSNP: rs765587961
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188183 SCV000241790 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MFSD8 gene. The T421I variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 8/33572 (0.02%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The T421I 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. However, 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 RCV000705254 SCV000834243 uncertain significance Neuronal ceroid lipofuscinosis 7 2022-10-13 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 421 of the MFSD8 protein (p.Thr421Ile). This variant is present in population databases (rs765587961, gnomAD 0.02%). 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: 206163). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MFSD8 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.
Natera, Inc. RCV001833123 SCV002084762 uncertain significance Late-infantile neuronal ceroid lipofuscinosis 2020-09-09 no assertion criteria provided clinical testing

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