ClinVar Miner

Submissions for variant NM_022445.4(TPK1):c.656A>G (p.Asn219Ser)

gnomAD frequency: 0.00001  dbSNP: rs371271054
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000437841 SCV000517229 pathogenic not provided 2015-06-17 criteria provided, single submitter clinical testing The N219S missense variant in the TPK1 gene has been reported previously in association with thiaminepyrophosphokinase deficiency in a patient who was compound heterozygous for N219S and a frameshiftvariant (Mayr et al. 2011). N219S occurs at a position that is conserved across species, in silico analysispredicts that N219S is probably damaging to the protein structure/function, and a missense variant in anearby residue (D222H) has also been reported in the Human Gene Mutation Database in association withthiamine pyrophosphokinase deficiency (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Therefore, we interpret N219S to be a pathogenic variant.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000023535 SCV001369604 pathogenic Childhood encephalopathy due to thiamine pyrophosphokinase deficiency 2020-04-02 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM2,PM3,PP2,PP3.
Invitae RCV000023535 SCV003256098 pathogenic Childhood encephalopathy due to thiamine pyrophosphokinase deficiency 2023-05-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPK1 function (PMID: 30483896). 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 TPK1 protein function. ClinVar contains an entry for this variant (Variation ID: 30572). This missense change has been observed in individual(s) with thiamine metabolism dysfunction syndrome (PMID: 22152682, 28747443). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs371271054, gnomAD 0.02%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 219 of the TPK1 protein (p.Asn219Ser).
Ambry Genetics RCV002513193 SCV003735974 uncertain significance Inborn genetic diseases 2022-05-25 criteria provided, single submitter clinical testing The c.656A>G (p.N219S) alteration is located in exon 9 (coding exon 8) of the TPK1 gene. This alteration results from a A to G substitution at nucleotide position 656, causing the asparagine (N) at amino acid position 219 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
OMIM RCV000023535 SCV000044826 pathogenic Childhood encephalopathy due to thiamine pyrophosphokinase deficiency 2011-12-09 no assertion criteria provided literature only

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