ClinVar Miner

Submissions for variant NM_033409.4(SLC52A3):c.62A>G (p.Asn21Ser) (rs199588390)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000191957 SCV000775600 uncertain significance Brown-Vialetto-Van Laere syndrome 1 2019-08-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 21 of the SLC52A3 protein (p.Asn21Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs199588390, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another SLC52A3 variant in several individuals affected with Brown-Vialetto-Van Laere syndrome and Fazio Londe syndrome (PMID: 22718020, 27702554, 29501408). One of these individuals was also homozygous for a variant (p.Pro141Thr) in a different gene, SLC52A2. However, the unaffected sibling was also homozygous for this second variant suggesting that SCL52A3 p.Asn21Ser was more likely to contribute to disease in this family. ClinVar contains an entry for this variant (Variation ID: 210012). Experimental studies have shown that this missense change results in a protein with significantly reduced riboflavin uptake, most likely as a result of its cellular mislocalization (PMID: 27702554). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000790977 SCV000930237 uncertain significance not specified 2019-04-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000790977 SCV000967532 uncertain significance not specified 2018-06-06 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asn21Ser variant in SLC52A3 has been reported in 2 individuals with Brown-Vialetto-Van La ere (BVVL) syndrome, a type of riboflavin transporter deficiency neuronopathy th at causes nerve damage including sensorineural hearing loss. One individual was homozygous (Udhayabanu 2016) for this variant and the other individual was compo und heterozygous with a second variant of uncertain significance (Dezfouli 2012) . This variant has been identified in 25/124008 of European chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs19 9588390). Although this variant has been seen in the general population, its fre quency is not high enough to rule out a pathogenic role. Computational predictio n tools and conservation analysis suggest that thep.Asn21Ser variant may impact the protein, though this information is not predictive enough to determine patho genicity. In vitro functional studies provide some evidence that the p.Asn21Ser variant may impact protein function, specifically riboflavin uptake by due to im paired trafficking and membrane targeting (Udhayabanu 2016). However, these type s of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Asn21Ser variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS3_Supporting, PM3_P.
GeneReviews RCV000191957 SCV000246207 pathogenic Brown-Vialetto-Van Laere syndrome 1 2015-03-17 no assertion criteria provided literature only

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