chr8-144360604-T-C

Position:

chr8-144360604-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM2PP3_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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 39577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144360604-T-C is described in UniProt as null. Variant chr8-144360604-T-C is described in UniProt as null. Variant chr8-144360604-T-C is described in UniProt as null. Variant chr8-144360604-T-C is described in UniProt as null. Variant chr8-144360604-T-C is described in UniProt as null. Variant chr8-144360604-T-C is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 126 alleles in male gnomad4_exome subpopulation. Median coverage is 46. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC52A2	NM_001363118.2 linkuse as main transcript	c.1016T>C	p.Leu339Pro	missense_variant	4/5	ENST00000643944.2	NP_001350047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC52A2	ENST00000643944.2 linkuse as main transcript	c.1016T>C	p.Leu339Pro	missense_variant	4/5		NM_001363118.2	ENSP00000496184	P1

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

GnomAD3 exomes

AF:

0.0000703

AC:

AN:

241950

Hom.:

AF XY:

0.0000683

AC XY:

AN XY:

131796

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000236

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	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 -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2023	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). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC52A2 protein function with a positive predictive value of 80%. 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -
Pathogenic, no assertion criteria provided	research	Duke University Health System Sequencing Clinic, Duke University Health System	Mar 25, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 03, 2023	PS3, PM2, PM3_Strong, PP3 -

SLC52A2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2019

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2022

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

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

MutationTaster

Benign

1.0

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

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

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

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