NM_001363118.2:c.1016T>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PP3_StrongPP5_Very_StrongBS1_Supporting

The NM_001363118.2(SLC52A2):c.1016T>C(p.Leu339Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,601,890 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L339L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

SLC52A2
NM_001363118.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 6.15

Publications

17 publications found

Variant links:

Genes affected

SLC52A2 (HGNC:30224): (solute carrier family 52 member 2) This gene encodes a membrane protein which belongs to the riboflavin transporter family. In humans, riboflavin must be obtained by intestinal absorption because it cannot be synthesized by the body. The water-soluble vitamin riboflavin is processed to the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) which then act as intermediaries in many cellular metabolic reactions. Paralogous members of the riboflavin transporter gene family are located on chromosomes 17 and 20. Unlike other members of this family, this gene has higher expression in brain tissue than small intestine. Alternative splicing of this gene results in multiple transcript variants encoding the same protein. Mutations in this gene have been associated with Brown-Vialetto-Van Laere syndrome 2 - an autosomal recessive progressive neurologic disorder characterized by deafness, bulbar dysfunction, and axial and limb hypotonia. [provided by RefSeq, Jul 2012]

SLC52A2 Gene-Disease associations (from GenCC):

Brown-Vialetto-van Laere syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

SLC52A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 8-144360604-T-C is Pathogenic according to our data. Variant chr8-144360604-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 39577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000187 (271/1449690) while in subpopulation NFE AF = 0.000236 (262/1110908). AF 95% confidence interval is 0.000212. There are 0 homozygotes in GnomAdExome4. There are 126 alleles in the male GnomAdExome4 subpopulation. Median coverage is 46. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC52A2	NM_001363118.2 link	c.1016T>C	p.Leu339Pro	missense_variant	Exon 4 of 5	ENST00000643944.2	NP_001350047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC52A2	ENST00000643944.2 link	c.1016T>C	p.Leu339Pro	missense_variant	Exon 4 of 5		NM_001363118.2	ENSP00000496184.2		Q9HAB3

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000703

AC:

AN:

241950

AF XY:

0.0000683

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000187

AC:

271

AN:

1449690

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

126

AN XY:

721568

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33446

American (AMR)

AF:

0.0000224

AC:

AN:

44592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86080

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000236

AC:

262

AN:

1110908

Other (OTH)

AF:

0.000116

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brown-Vialetto-van Laere syndrome 2

Pathogenic:7Other:1

Jan 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 25, 2015

Duke University Health System Sequencing Clinic, Duke University Health System

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Aug 30, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM2, PM3_Strong, PP3 -

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC52A2 protein function with a positive predictive value of 95%. 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. -

Jun 11, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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 -

SLC52A2-related disorder

Pathogenic:1

Jun 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method: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. -

Inborn genetic diseases

Pathogenic:1

Dec 11, 2019

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

not provided

Pathogenic:1

Jun 26, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D;.;D;D;D;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Pathogenic

3.2

M;M;.;M;M;M;M

PhyloP100

6.2

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.5

D;D;.;D;D;D;.

REVEL

Pathogenic

0.82

Sift

Uncertain

0.011

D;D;.;D;D;D;.

Sift4G

Uncertain

0.0020

D;D;.;D;D;D;.

Polyphen

1.0

D;D;.;D;D;D;D

Vest4

0.97

MVP

0.76

MPC

0.69

ClinPred

0.90

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.93

gMVP

0.93

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over