Submissions for variant NM_025243.4(SLC19A3):c.337T>C (p.Tyr113His)

gnomAD frequency: 0.00004  dbSNP: rs145999922

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000408622	SCV000484435	likely pathogenic	Biotin-responsive basal ganglia disease	2014-10-08	criteria provided, single submitter	clinical testing	This heterozygous variant results in a substitution of a tyrosine for a histidine at amino acid position 113, NP_079519.1(SLC19A3): p.(Tyr113His). The tyrosine at this position is moderately/highly conserved and is situated in a transmembrane domain. Grantham assessment is likely deleterious due to both amino acid properties and conservation. In-silico software predicts this variant to be disease-causing. This variant has been reported in normal populations occurring at a frequency of 1 in 6500 individuals, which would be consistent with a carrier frequency for a rare recessive condition.It was identified in trans with a second pathogenic variant in this gene in a child with clinical and biochemical evidence of the disease.
Invitae	RCV000408622	SCV000762304	pathogenic	Biotin-responsive basal ganglia disease	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 113 of the SLC19A3 protein (p.Tyr113His). This variant is present in population databases (rs145999922, gnomAD 0.009%). This missense change has been observed in individual(s) with early-onset progressive encephalopathy and/or thiamine transporter dysfunction syndrome (PMID: 26863430, 26938784). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 369673). 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 SLC19A3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001546114	SCV001765572	likely pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Identified in additional patients with seizures, dystonia, and other history consistent with an SLC19A3-related disorder who also harbored a second missense or promoter region copy number variant on the opposite allele, or for whom no second variant could be identified (Flones et al., 2016; Wesol-Kucharska et al., 2021); 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: 28696212, 28402605, 26863430, 29453417, 26938784, 28832562, 34631424)
Fulgent Genetics, Fulgent Genetics	RCV000408622	SCV002794795	likely pathogenic	Biotin-responsive basal ganglia disease	2022-04-19	criteria provided, single submitter	clinical testing