ClinVar Miner

Submissions for variant NM_033409.4(SLC52A3):c.1238T>C (p.Val413Ala) (rs267606687)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000000167 SCV000657509 uncertain significance Brown-Vialetto-Van Laere syndrome 1 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 413 of the SLC52A3 protein (p.Val413Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs267606687, ExAC 0.007%). This variant has been observed in individual(s) with with Brown-Vialetto-Van Laere Syndrome (BVVLS) (PMID: 20206331, 22824638, 26443808, 27777325). ClinVar contains an entry for this variant (Variation ID: 144). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826040 SCV000967531 uncertain significance not specified 2018-04-04 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val413Ala variant in SLC53A3 has been reported in the compound heterozygous state in 3 pr obands with Brown-Vialetto-Van Laere syndrome (BVVLS; Green 2010, Ciccolella 201 2, Davis 2016). It has also been identified in 3/64554 European chromosomes by t he Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org; dbSNP rs267606687). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predi ction tools and conservation analysis suggest that the variant may not impact th e protein, though this information is not predictive enough to rule out pathogen icity. In summary, while there is some suspicion for a pathogenic role, the clin ical significance of the p.Val413Ala variant is uncertain. ACMG/AMP Criteria app lied: PM2; PM3_supporting; BP4.
OMIM RCV000000167 SCV000020310 pathogenic Brown-Vialetto-Van Laere syndrome 1 2010-03-12 no assertion criteria provided literature only
GeneReviews RCV000000167 SCV000246226 pathogenic Brown-Vialetto-Van Laere syndrome 1 2015-03-17 no assertion criteria provided literature only

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