rs398124641

chr8-144360408-G-Achr8-144360408-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001363118.2(SLC52A2):c.916G>A(p.Gly306Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,607,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G306E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SLC52A2 NM_001363118.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.65

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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, 8 uncertain in NM_001363118.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-144360409-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 246558.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 8-144360408-G-A is Pathogenic according to our data. Variant chr8-144360408-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 35470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144360408-G-A is described in UniProt as null. Variant chr8-144360408-G-A is described in UniProt as null. Variant chr8-144360408-G-A is described in UniProt as null. Variant chr8-144360408-G-A is described in UniProt as null. Variant chr8-144360408-G-A is described in UniProt as null. Variant chr8-144360408-G-A is described in Lovd as [Pathogenic]. Variant chr8-144360408-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC52A2	NM_001363118.2	c.916G>A	p.Gly306Arg	missense_variant	3/5	ENST00000643944.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC52A2	ENST00000643944.2	c.916G>A	p.Gly306Arg	missense_variant	3/5		NM_001363118.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152258 Hom.: 0 Cov.: 33

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000407 AC: 10 AN: 245830 Hom.: 0 AF XY: 0.0000523 AC XY: 7 AN XY: 133780

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 169 AN: 1454940 Hom.: 0 Cov.: 31 AF XY: 0.000104 AC XY: 75 AN XY: 724038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74386

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: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brown-Vialetto-van Laere syndrome 2 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 306 of the SLC52A2 protein (p.Gly306Arg). This variant is present in population databases (rs398124641, gnomAD 0.009%). This missense change has been observed in individuals with the clinical features of Brown-Vialetto-Van Laere syndrome (BVVLS) (PMID: 22740598, 24253200, 24616084, 25133958, 26669662). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 35470). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC52A2 function (PMID: 24253200, 24616084). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 30, 2014	The p.Gly306Arg variant in SLC52A2 has been reported in 8 homozygous and 6 compound heterozygous individuals with the clinical features of Brown-Vialetto-Van Laere syndrome and was found to segregate with disease in >10 affected individuals from 6 families (Johnson 2012, Foley 2014, Srour 2014, Fogel 2014). This variant was also identified in 1/16592 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs398124641). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies indicate that this variant may decrease protein levels (Foley 2014). Additional computational prediction tools and conservation analysis suggest that the p.Gly206Arg variant may impact splicing through the creation of a novel 3' splice site; however this information is not predictive enough to be conclusive. In summary, this variant meets our criteria to be classified as pathogenic for of Brown-Vialetto-Van Laere syndrome in an autosomal recessive manner based upon segregation studies and biallelic occurrence in many cases. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a glycine to an arginine (exon 3). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygote). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (DUF1011 domain) (N) 0704 - Comparable variant has low previous evidence for pathogenicity (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar).(P) 0901 - Strong evidence for segregation with disease in multiple families (PMID 24616084, PMID 24253200) (P) 1002 - Moderate functional evidence supporting abnormal protein function. Reduced protein expression and uptake was demonstrated in cells expressing this variant (PMID 24253200) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant in the Lebanese population -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2022	Published functional studies demonstrate a damaging effect (decreased SLC52A2 protein expression and reduction in 3 H-riboflavin transport activity) (Foley et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25133958, 28251916, 26669662, 22740598, 34602496, 30377535, 29913018, 26072523, 32773395, 24253200) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2022

The p.G306R pathogenic mutation (also known as c.916G>A), located in coding exon 2 of the SLC52A2 gene, results from a G to A substitution at nucleotide position 916. The glycine at codon 306 is replaced by arginine, an amino acid with dissimilar properties. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration has been found to segregate among affected relatives in the one Lebanese family (Srour M et al. Muscle Nerve, 2014 Nov;50:775-9) and is considered a Lebanese founder mutation (Megarbane A et al. J Neuromuscul Dis, 2022;9:193-210; Foley AR et al. Brain, 2014 Jan;137:44-56). This alteration has also been detected in the homozygous state, and in the compound heterozygous state with another pathogenic SLC2A2 mutation, in multiple unrelated individuals (Montaut S et al. JAMA Neurol, 2018 10;75:1234-1245; Guissart C et al. Eur J Hum Genet, 2016 08;24:1154-9; Fan J et al. Cerebellum Ataxias, 2018 Oct;5:12; Bansagi B et al. Neurology, 2017 Mar;88:1226-1234; Allison T et al. J Child Neurol, 2017 05;32:528-532; Foley AR et al. Brain, 2014 Jan;137:44-56; Fogel BL et al. JAMA Neurol, 2014 Oct;71:1237-46; Johnson JO et al. Brain, 2012 Sep;135:2875-82). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D;D;.;D;D;D;D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.3	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D;D;D;D;D;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.96
MutPred		0.96		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);.;Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP		0.81
MPC		0.59
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs398124641; hg19: chr8-145584068;