Submissions for variant NM_033409.4(SLC52A3):c.395G>A (p.Arg132Gln)

gnomAD frequency: 0.00022  dbSNP: rs142157418

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000557473	SCV000657523	uncertain significance	Brown-Vialetto-van Laere syndrome 1	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 132 of the SLC52A3 protein (p.Arg132Gln). This variant is present in population databases (rs142157418, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SLC52A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 476610). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825236	SCV000966520	likely benign	not specified	2018-05-10	criteria provided, single submitter	clinical testing	p.Arg132Gln in Exon 2 of SLC52A3: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, more than 10 mammals have a Glutamine (Gln) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. Additionally, this varia nt has been identified in 0.03% (38/126634) of European chromosomes by the Genom e Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142157 418). ACMG/AMP Criteria applied: PM2, BP4_Strong
GeneDx	RCV001540821	SCV001758749	uncertain significance	not provided	2019-07-15	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; A different missense substitution at the same position (R132W) has been reported previously in association with Brown-Vialetto-Van Laere syndrome (Stenson et al., 2014); Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002377169	SCV002624036	uncertain significance	Inborn genetic diseases	2021-03-23	criteria provided, single submitter	clinical testing	The p.R132Q variant (also known as c.395G>A), located in coding exon 1 of the SLC52A3 gene, results from a G to A substitution at nucleotide position 395. The arginine at codon 132 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.