1-169477447-C-T

Position:

• chr1-169477447-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SLC19A2 NM_006996.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 ClinVar as [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/exons	MANE	Protein	UniProt
SLC19A2	NM_006996.3	c.515G>A	p.Gly172Asp	missense_variant	2/6	ENST00000236137.10	NP_008927.1
SLC19A2	NM_001319667.1	c.205-7261G>A		intron_variant			NP_001306596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC19A2	ENST00000236137.10	c.515G>A	p.Gly172Asp	missense_variant	2/6	1	NM_006996.3	ENSP00000236137.5
SLC19A2	ENST00000367804.4	c.205-7261G>A		intron_variant		1		ENSP00000356778.3
SLC19A2	ENST00000646596.1	c.515G>A	p.Gly172Asp	missense_variant	2/6			ENSP00000494404.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251404 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135888

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 SAS 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: 11 AN: 1461894 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 13, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 10, 2018	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1999	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2023	Published functional studies resulted in absent thiamine transport and retention of the protein in the endoplasmic reticulum, demonstrating a damaging effect (Baron et al., 2002); 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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.2	M;M;.
PrimateAI	Uncertain	0.76	T
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	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.94

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

Other links and lift over

dbSNP: rs28937595; hg19: chr1-169446685;