ClinVar Miner

Submissions for variant NM_033409.4(SLC52A3):c.1371C>G (p.Phe457Leu) (rs145431028)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493823 SCV000582674 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SLC52A3 gene. The F457L variant has been previously reported in both the heterozygous and homozygous states in individuals with Brown-Vialetto-Van Laere syndrome (Green et al., 2010; Bansagi et al., 2017). While not observed in the homozygous state, the F457L variant is observed in 93/119820 (0.08%) alleles from individuals of European background and in 100/264808 (0.04%) alleles globally in large population cohorts (Lek et al., 2016). This 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 a deleterious effect. Therefore, based on the currently available information, it is unclear whether the F457L variant is a pathogenic variant or a rare benign variant.
Invitae RCV000191974 SCV000657514 uncertain significance Brown-Vialetto-Van Laere syndrome 1 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 457 of the SLC52A3 protein (p.Phe457Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs145431028, ExAC 0.08%). This variant has been reported in the homozygous state in individuals affected with Brown-Vialetto-Van Laere syndrome (BVVLS) (PMID: 20206331, 22740598). It has been reported in several individuals with BVVLS, however a second variant was not identified in these individuals (PMID:28251916,29053833). ClinVar contains an entry for this variant (Variation ID: 210029). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
GeneReviews RCV000191974 SCV000246230 pathogenic Brown-Vialetto-Van Laere syndrome 1 2015-03-17 no assertion criteria provided literature only

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