NM_006996.3:c.515G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_006996.3(SLC19A2):c.515G>A(p.Gly172Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,020 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G172V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SLC19A2
NM_006996.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.57

Publications

15 publications found

Variant links:

Genes affected

SLC19A2 (HGNC:10938): (solute carrier family 19 member 2) This gene encodes the thiamin transporter protein. Mutations in this gene cause thiamin-responsive megaloblastic anemia syndrome (TRMA), which is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anemia and sensorineural deafness. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

SLC19A2 Gene-Disease associations (from GenCC):

thiamine-responsive megaloblastic anemia syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp

SLC19A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 1-169477447-C-T is Pathogenic according to our data. Variant chr1-169477447-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169477447-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169477447-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169477447-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169477447-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169477447-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 5957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC19A2	NM_006996.3 link	c.515G>A	p.Gly172Asp	missense_variant	Exon 2 of 6	ENST00000236137.10	NP_008927.1	O60779-1A0A024R928
SLC19A2	NM_001319667.1 link	c.205-7261G>A		intron_variant	Intron 1 of 4		NP_001306596.1	O60779-2A0A024R8Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC19A2	ENST00000236137.10 link	c.515G>A	p.Gly172Asp	missense_variant	Exon 2 of 6	1	NM_006996.3	ENSP00000236137.5	O60779-1
SLC19A2	ENST00000367804.4 link	c.205-7261G>A		intron_variant	Intron 1 of 4	1		ENSP00000356778.3	O60779-2
SLC19A2	ENST00000646596.1 link	c.515G>A	p.Gly172Asp	missense_variant	Exon 2 of 6			ENSP00000494404.1	A0A2R8Y5B5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251404

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness

Pathogenic:3

Jul 01, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 10, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC19A2 c.515G>A (p.Gly172Asp) missense variant has been reported in three studies in which it is found in a total of five probands with thiamine-responsive megaloblastic anemia syndrome (TRMA) including in two in a homozygous state and in three in a compound heterozygous state (of whom two are siblings) (Labay et al. 1999; Alzahrani et al. 2006; Bergmann et al. 2009). Control data are unavailable for this variant, which is reported at a frequency of 0.00001 in the European (non-Finnish) population of the Genome Aggregation Database based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. More than one functional study in cultured cells transfected with variant p.Gly172Asp protein, demonstrated significantly decreased thiamine uptake compared to cells transfected with wild type protein (Balamurugan et al. 2002; Baron et al. 2002; Subramanian et al. 2007). The localization of the variant protein compared to wild type differed between studies. Baron et al. (2002) reports that the p.Gly172Asp variant protein could not be detected under normal physiological conditions, but at lower temperatures was shown to be localized in the cytoplasm and endoplasmic reticulum (compared to wild type located in the cytoplasm and at the plasma membrane), and demonstrated partial N-glycosylation and altered protein folding. Subramanian et al. (2007) reports that the p.Gly172Asp variant protein was absent from the cytoplasmic fraction and shown to be completely retained within the endoplasmic reticulum. Based on the collective evidence, the p.Gly172Asp variant is classified as pathogenic for thiamine-responsive megaloblastic anemia syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Mar 07, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies resulted in absent thiamine transport and retention of the protein in the endoplasmic reticulum, demonstrating a damaging effect (PMID: 12435857); Not observed at significant frequency in large population cohorts (gnomAD); 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: 12065289, 31589614, 31095747, 17463047, 23454484, 29450569, 19643445, 22369132, 35686496, 33571483, 10874303, 28371426, 15871139, 19619756, 10391221, 33816400, 12435857) -

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 172 of the SLC19A2 protein (p.Gly172Asp). This variant is present in population databases (rs28937595, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive thiamine-responsive megaloblastic anemia (PMID: 9856490, 10391221, 19643445, 33816400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5957). 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 SLC19A2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SLC19A2 function (PMID: 12065289, 12435857). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;D;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

3.2

M;M;.

PhyloP100

7.6

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.2

D;.;.

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0020

D;.;.

Sift4G

Uncertain

0.0050

D;.;.

Polyphen

0.99

D;D;.

Vest4

0.98

MutPred

0.95

Loss of catalytic residue at V171 (P = 0.2566);Loss of catalytic residue at V171 (P = 0.2566);Loss of catalytic residue at V171 (P = 0.2566);

MVP

0.95

MPC

0.79

ClinPred

0.99

GERP RS

5.3

Varity_R

0.87

gMVP

0.94

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

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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