Submissions for variant NM_001363118.2(SLC52A2):c.1016T>C (p.Leu339Pro)

gnomAD frequency: 0.00008  dbSNP: rs148234606

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236444	SCV000292691	pathogenic	not provided	2022-06-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced or absent riboflavin transport activity (Haack et al., 2012; Foley et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22864630, 24253200, 27148561, 28251916, 25798182, 27702554, 25807286, 23107375, 32909658)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000032777	SCV000652647	pathogenic	Brown-Vialetto-van Laere syndrome 2	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 339 of the SLC52A2 protein (p.Leu339Pro). This variant is present in population databases (rs148234606, gnomAD 0.01%). This missense change has been observed in individuals with Brown-Vialetto-Van Laere syndrome (PMID: 22864630, 24253200, 25807286, 27148561). ClinVar contains an entry for this variant (Variation ID: 39577). 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 expected to disrupt SLC52A2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC52A2 function (PMID: 22864630, 24253200, 25798182). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000624303	SCV000742384	pathogenic	Inborn genetic diseases	2019-12-11	criteria provided, single submitter	clinical testing	The p.L339P variant (also known as c.1016T>C), located in coding exon 3 of the SLC52A2 gene, results from a T to C substitution at nucleotide position 1016. The leucine at codon 339 is replaced by proline, an amino acid with similar properties. This alteration has been reported in the compound heterozygous state in multiple individuals diagnosed with Brown-Vialetto-Van Laere syndrome (Foley AR et al. Brain, 2014 Jan;137:44-56; Haack TB et al. J. Inherit. Metab. Dis., 2012 Nov;35:943-8; Bansagi B et al. Neurology, 2017 Mar;88:1226-1234; Manole A et al. Brain, 2017 11;140:2820-2837; Petrovski S et al. Cold Spring Harb Mol Case Stud, 2015 Oct;1:a000257). In vitro functional analysis of this alteration in HEK239 cells showed a significant decrease in hRFT3 riboflavin transporter activity compared to wild type cells (Haack TB et al. J. Inherit. Metab. Dis., 2012 Nov;35:943-8). It was additionally shown that this alteration leads to decreased expression in plasma membranes and abolished uptake of 3H-riboflavin (Foley AR et al. Brain, 2014 Jan;137:44-56). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000032777	SCV002020714	pathogenic	Brown-Vialetto-van Laere syndrome 2	2022-08-30	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000032777	SCV002768347	pathogenic	Brown-Vialetto-van Laere syndrome 2	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_001253816.1(SLC52A2):c.1016T>C in exon 4 of the SLC52A2 gene. This substitution is predicted to create a moderate amino acid change from a leucine to a proline at position 339 of the protein; NP_001240745.1(SLC52A2):p.(Leu339Pro). The leucine at this position has moderate conservation (100 vertebrates, UCSC), and is located within a DUF1011 (NCBI, PDB). In silico software predicts this variant to be damaging (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is present in the gnomAD population database at a global population frequency of 0.0066% (18 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.013%. This variant has been previously reported as pathogenic in patients with Brown-Vialetto-Van Laere syndrome (ClinVar, Petrovski, S. et al. (2015), Haack, T. B. et al. (2012)). It has also been shown to segregate with disease in one family (Foley, A. R. et al. (2014)). In addition, functional studies show that this variant causes significantly reduced riboflavin uptake and abolishes protein expression (Foley, A. R. et al. (2014)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Baylor Genetics	RCV000032777	SCV003835237	pathogenic	Brown-Vialetto-van Laere syndrome 2	2022-06-11	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000032777	SCV003932291	pathogenic	Brown-Vialetto-van Laere syndrome 2	2023-02-03	criteria provided, single submitter	clinical testing	PS3, PM2, PM3_Strong, PP3
OMIM	RCV000032777	SCV000056541	pathogenic	Brown-Vialetto-van Laere syndrome 2	2014-01-01	no assertion criteria provided	literature only
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000032777	SCV000221313	pathogenic	Brown-Vialetto-van Laere syndrome 2	2015-03-25	no assertion criteria provided	research
GeneReviews	RCV000032777	SCV000246249	not provided	Brown-Vialetto-van Laere syndrome 2		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004755754	SCV005362029	pathogenic	SLC52A2-related disorder	2024-06-04	no assertion criteria provided	clinical testing	The SLC52A2 c.1016T>C variant is predicted to result in the amino acid substitution p.Leu339Pro. This variant has been reported to be causative for Brown-Vialetto-van Laere Syndrome (Haack et al. 2012. PubMed ID: 22864630; Foley et al. 2014. PubMed ID: 24253200). A functional study showed that this variant significantly decreased the riboflavin transporter 3 activity (Haack et al. 2012. PubMed ID: 22864630). In addition, at PreventionGenetics, we have observed this variant in the compound heterozygous state with a frameshift pathogenic variant in trans in a different patient with Brown-Vialetto-van Laere Syndrome. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.