ClinVar Genomic variation as it relates to human health

SLC52A3: PM2, PM3:Supporting, PP3

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 457 of the SLC52A3 protein (p.Phe457Leu). This variant is present in population databases (rs145431028, gnomAD 0.08%). This missense change has been observed in individuals with Brown-Vialetto-Van Laere syndrome (BVVLS) (PMID: 20206331, 22740598, 28251916, 29053833). ClinVar contains an entry for this variant (Variation ID: 210029). 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 SLC52A3 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.

The c.1371C>G (p.F457L) alteration is located in exon 5 (coding exon 4) of the SLC52A3 gene. This alteration results from a C to G substitution at nucleotide position 1371, causing the phenylalanine (F) at amino acid position 457 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Variant summary: C20orf54 c.1371C>G (p.Phe457Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 269176 control chromosomes (gnomAD). c.1371C>G has been reported in the literature in individuals affected with Brown-Vialetto Laere Syndrome without strong evidence of causality (Bansagi_2017, Green_2010, Johnson_2012, Manole_2017). These reports do not provide unequivocal conclusions about association of the variant with Brown-Vialetto Laere Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20206331, 22740598, 29053833, 28251916). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27777325, 20206331, 28251916, 22740598, 23107375, 31959559, 29053833, 26072523)

Variant interpreted as Uncertain significance and reported on 09-02-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.