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

gnomAD frequency: 0.00006  dbSNP: rs199588390

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000191957	SCV000775600	pathogenic	Brown-Vialetto-van Laere syndrome 1	2023-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 21 of the SLC52A3 protein (p.Asn21Ser). This variant is present in population databases (rs199588390, gnomAD 0.02%). This missense change has been observed in individuals with Brown-Vialetto-Van Laere syndrome and/or Fazio Londe syndrome (PMID: 27702554, 33189404, 33325104). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 210012). 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 SLC52A3 protein function. Experimental studies have shown that this missense change affects SLC52A3 function (PMID: 27702554). For these reasons, this variant has been classified as Pathogenic.
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, Mass General Brigham 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.
GeneDx	RCV001589066	SCV001826288	likely pathogenic	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on protein localization; protein was retained in intracellular vesicles, leading to a reduction in riboflavin intake (Udhayabanu T et al., 2016); 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: 29501408, 27702554, 31959559, 33325104, 22718020, 33189404, 34426522, 36511838)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001589066	SCV002011178	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362997	SCV002657219	uncertain significance	Inborn genetic diseases	2020-10-20	criteria provided, single submitter	clinical testing	The p.N21S variant (also known as c.62A>G), located in coding exon 1 of the SLC52A3 gene, results from an A to G substitution at nucleotide position 62. The asparagine at codon 21 is replaced by serine, an amino acid with highly similar properties. This variant was detected in two individuals with Brown-Vialetto-Van Laere syndrome; one individual was homozygous, and the other was compound heterozygous with a second variant in SLC52A3 (p.A312V, c.935C>T) (Gowda VK et al. Brain Dev, 2018 Aug;40:582-586; Dezfouli MA et al. J Hum Genet, 2012 Sep;57:613-7). In addition, this variant was detected in the homozygous state in an individual with Fazio-Londe syndrome, who also had a homozygous alteration in SLC52A2 (p.P141T, c.421C>A) (Udhayabanu T et al. Clin Chim Acta, 2016 Nov;462:210-214). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000191957	SCV003801229	likely pathogenic	Brown-Vialetto-van Laere syndrome 1	2023-01-11	criteria provided, single submitter	clinical testing	Variant summary: SLC52A3 (aka. C20orf54) c.62A>G (p.Asn21Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 (i.e. 41 heterozygous carriers) in 279628 control chromosomes. This frequency doesn't allow clear conclusions about variant significance. The variant, c.62A>G, has been reported in the literature in several homozygous and compound heterozygous individuals affected with Brown-Vialetto Laere- (BVVL) and Fazio-Londe (FL) syndrome (Udhayabanu_2016, Gowda_2018, Gayathri_2021, Dezfouli_2012), and in several cases improvement after riboflavin supplementation was described (Udhayabanu_2016, Gowda_2018, Gayathri_2021). In one of these families the variant was reported in a homozygous BLLV patient, who also carried another homozygous variant in a different riboflavin transporter gene (SLC52A2 c.421C>A (p.P141T)), which could contribute to the patient's phenotype (Udhayabanu_2016). On the other hand, the variant was also reported in a family in 3 homozygotes, where one was affected with BVVL, one with isolated hearing loss, and a third homozygous family member was apparently unaffected (Khani_2021); in this family the variant was also found in 4 heterozygotes, and none of them was diagnosed with BVVL or was noted to have hearing problems. In another family, where 3 compound heterozygotes were diagnosed with BVVL, the variant was also found in 2 heterozygotes, and one of them was affected with BVVL, while the other had isolated hearing loss (Khani_2021). Authors of this study concluded that the variant might have variable expressivity and incomplete penetrance, where environmental insults and putative causative mutations in other genes may contribute to these variable presentations (Khani_2021). These data indicate that the variant is very likely to be associated with disease, although it's expressivity and penetrance may be variable. One of these publications also reported experimental evidence evaluating an impact on protein function, and demonstrated mislocalization for the variant protein when transfected into neuronal- and intestinal cell lines, in addition, riboflavin uptake was almost completely abolished, when measured in the transfected intestinal cell line (Udhayabanu_2016). Six submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 mostly without evidence for independent evaluation, and classified the variant as likely pathogenic (n=1) or VUS (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV001589066	SCV003819176	pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417696	SCV004114859	likely pathogenic	SLC52A3-related condition	2023-01-09	criteria provided, single submitter	clinical testing	The SLC52A3 c.62A>G variant is predicted to result in the amino acid substitution p.Asn21Ser. This variant has been reported in the homozygous state or compound heterozygous with a second SLC52A3 variant in multiple individuals with Brown-Vialetto-Van Laere syndrome (BVVLS) or Fazio-Londre syndrome (FLS) (gene referred to as C20orf54 in Dezfouli et al. 2012. PubMed ID: 22718020; Udhayabanu et al. 2016. PubMed ID: 27702554; Gowda et al. 2018. PubMed ID: 29501408; Khani et al. 2020. PubMed ID: 33189404; Gayathri et al. 2021. PubMed ID: 33325104). The patient reported by Udhayabanu et al. was also homozygous for a variant in the SLC52A2 gene (c.421C>A, p.Pro141Thr); however, in functional studies the SLC52A2 p.Pro141Thr substitution behaved similarly to control whereas the SLC52A3 p.Asn21Ser substitution lead to greatly reduced riboflavin uptake and absent cell surface expression (Udhayabanu et al. 2016. PubMed ID: 27702554). This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-746357-T-C). Taken together, this variant is interpreted as likely pathogenic.
GeneReviews	RCV000191957	SCV000246207	not provided	Brown-Vialetto-van Laere syndrome 1		no assertion provided	literature only