rs199588390

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_033409.4(SLC52A3):c.62A>G(p.Asn21Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N21N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SLC52A3
NM_033409.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4O:1

Conservation

PhyloP100: 7.95

Variant links:

Genes affected

SLC52A3 (HGNC:16187): (solute carrier family 52 member 3) This gene encodes a riboflavin transporter protein that is strongly expressed in the intestine and likely plays a role in intestinal absorption of riboflavin. The protein is predicted to have eleven transmembrane domains and a cell surface localization signal in the C-terminus. Mutations at this locus have been associated with Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease. [provided by RefSeq, Mar 2012]

SLC52A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_033409.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

PP5

Variant 20-765713-T-C is Pathogenic according to our data. Variant chr20-765713-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210012.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=4, not_provided=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC52A3	NM_033409.4 linkuse as main transcript	c.62A>G	p.Asn21Ser	missense_variant	2/5	ENST00000645534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC52A3	ENST00000645534.1 linkuse as main transcript	c.62A>G	p.Asn21Ser	missense_variant	2/5		NM_033409.4	P1	Q9NQ40-1

Frequencies

GnomAD3 genomes

AF:

0.0000593

AC:

AN:

151696

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000727

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000161

AC:

AN:

248370

Hom.:

AF XY:

0.000164

AC XY:

AN XY:

134458

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.000197

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000225

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000133

AC:

194

AN:

1461724

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000150

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000593

AC:

AN:

151814

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74184

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000947

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.0000955

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2023	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Brown-Vialetto-van Laere syndrome 1

Pathogenic:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 22, 2023	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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 06, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -

SLC52A3-related condition

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2023

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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.17

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T;.;T;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.79

D;D;D;D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.9

M;M;M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

Polyphen

1.0

D;D;D;D;D

Vest4

0.88, 0.89

MVP

0.87

MPC

0.84

ClinPred

0.65

GERP RS

5.6

Varity_R

0.34

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over