Submissions for variant NM_001363118.2(SLC52A2):c.935T>C (p.Leu312Pro)

gnomAD frequency: 0.00004  dbSNP: rs754320812

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224069	SCV000281303	pathogenic	not provided	2016-05-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000224069	SCV000292690	likely pathogenic	not provided	2016-04-15	criteria provided, single submitter	clinical testing	The L312P variant in the SLC52A2 gene has been reported previously in two unrelated individuals with Brown-Vialetto-Van Laere syndrome who were heterozygous for the L312P variant and another variant (Foley et al., 2014). The L312P variant was also reported in a study that identified the variant in an individual with an abnormality of the nervous system, however, no additional information was provided (Retterer et al., 2015). Expression studies show the L312P varaint caused reduced riboflavin uptake and reduced riboflavin transporter protein expression (Foley et al., 2014). The L312P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L312P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. The L312P variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Ambry Genetics	RCV000623325	SCV000742383	pathogenic	Inborn genetic diseases	2023-08-16	criteria provided, single submitter	clinical testing	The c.935T>C (p.L312P) alteration is located in exon 3 (coding exon 2) of the SLC52A2 gene. This alteration results from a T to C substitution at nucleotide position 935, causing the leucine (L) at amino acid position 312 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.003% (7/276638) total alleles studied. The highest observed frequency was 0.014% (1/7158) of Other alleles. This alteration has been reported in the homozygous state, and in conjunction with another alteration in SLC52A2, in multiple individuals with clinical features of Brown-Vialetto-Van Laere syndrome (Foley, 2014; Manole, 2017; Allison, 2017; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In vitro functional analysis of the p.L312P alteration showed a moderate decrease in 3H-transport activity compared with wild-type SLC52A2 (Foley, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Invitae	RCV000191986	SCV000772310	pathogenic	Brown-Vialetto-van Laere syndrome 2	2023-10-08	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 312 of the SLC52A2 protein (p.Leu312Pro). This variant is present in population databases (rs754320812, gnomAD 0.005%). This missense change has been observed in individuals with Brown-Vialetto-Van Laere syndrome (PMID: 24253200, 29053833). ClinVar contains an entry for this variant (Variation ID: 210041). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC52A2 protein function. Experimental studies have shown that this missense change affects SLC52A2 function (PMID: 24253200). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000191986	SCV002766461	likely pathogenic	Brown-Vialetto-van Laere syndrome 2	2022-11-22	criteria provided, single submitter	clinical testing	Variant summary: GPR172A (SLC52A2) c.935T>C (p.Leu312Pro) 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 2.5e-05 in 276638 control chromosomes (gnomAD). c.935T>C has been reported in the literature as a biallelic genotype in individuals affected with Brown-Vialetto Laere Syndrome (e.g. Foley_2014, Manole_2017, Marioli_2020). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Foley_2014, Console_2022). The most pronounced variant effect results in approximately 40-50% of normal 3H-Riboflavin transport activity and displays a reduced binding affinity compared to the wildtype protein. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as either pathogenic (n=2) or likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneReviews	RCV000191986	SCV000246247	not provided	Brown-Vialetto-van Laere syndrome 2		no assertion provided	literature only