rs121917884

chr2-227688216-T-C

Variant summary

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

The NM_025243.4(SLC19A3):c.1264A>G(p.Thr422Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,778 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T422P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC19A3 NM_025243.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.55

Genes affected

SLC19A3 (HGNC:16266): (solute carrier family 19 member 3) This gene encodes a ubiquitously expressed transmembrane thiamine transporter that lacks folate transport activity. Mutations in this gene cause biotin-responsive basal ganglia disease (BBGD); a recessive disorder manifested in childhood that progresses to chronic encephalopathy, dystonia, quadriparesis, and death if untreated. Patients with BBGD have bilateral necrosis in the head of the caudate nucleus and in the putamen. Administration of high doses of biotin in the early progression of the disorder eliminates pathological symptoms while delayed treatment results in residual paraparesis, mild cognitive disability, or dystonia. Administration of thiamine is ineffective in the treatment of this disorder. Experiments have failed to show that this protein can transport biotin. Mutations in this gene also cause a Wernicke's-like encephalopathy.[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity S19A3_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_025243.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-227688216-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3064134.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 2-227688216-T-C is Pathogenic according to our data. Variant chr2-227688216-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227688216-T-C is described in Lovd as [Pathogenic]. Variant chr2-227688216-T-C is described in Lovd as [Pathogenic]. Variant chr2-227688216-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC19A3	NM_025243.4	c.1264A>G	p.Thr422Ala	missense_variant	5/6	ENST00000644224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC19A3	ENST00000644224.2	c.1264A>G	p.Thr422Ala	missense_variant	5/6		NM_025243.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461778 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotin-responsive basal ganglia disease Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 13, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 15, 2019	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed to segregate with biotin-responsive basal ganglia disease in multiple families (PMID: 15871139, 23742248, 27749535) and has also been observed in individuals with biotin-responsive basal ganglia disease (PMID: 24166474, 23742248). ClinVar contains an entry for this variant (Variation ID: 4563). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 422 of the SLC19A3 protein (p.Thr422Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2016	The T422A pathogenic variant in the SLC19A3 gene has been reported previously in association with biotin-responsive basal ganglia disease (BBGD) in multiple consanguineous families, and has been described as a founder mutation in the Saudi population (Zeng et al., 2005; Distelmaier et al., 2014; Alfadhel et al., 2013). The T422A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T422A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T422A as a pathogenic variant. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2020

The c.1264A>G (p.T422A) alteration is located in exon 5 (coding exon 4) of the SLC19A3 gene. This alteration results from an A to G substitution at nucleotide position 1264, causing the threonine (T) at amino acid position 422 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the SLC19A3 c.1264A>G alteration was not observed, with coverage at this position. This mutation has been identified in several Saudi Arabian individuals in the homozygous state with biotin-responsive basal ganglia disease (Zeng, 2005; Alfadhel, 2013; Distelmaier, 2014; Aljabri, 2016; Algahtani, 2017). The p.T422A alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type) Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.0	H;H;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.53	T
Polyphen		0.99	D;D;.
Vest4		0.86
MutPred		0.96		Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);.;
MVP		0.98
MPC		0.13
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.74

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: rs121917884; hg19: chr2-228552932;