ClinVar Miner

Submissions for variant NM_006996.3(SLC19A2):c.515G>A (p.Gly172Asp) (rs28937595)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486790 SCV000567516 pathogenic not provided 2015-08-23 criteria provided, single submitter clinical testing The G172D variant in the SLC19A2 gene has been reported previously in the homozygous state inmultiple individuals in a reportedly nonconsanguineous Italian family with thiamine-responsive megaloblasticanemia (Labey et al., 1999). Functional studies of G172D indicate absent thiamine transport and impairedthiamine uptake, most likely not related to impaired trafficking of the protein to the cell membrane (Baronet al., 2002; Balamurugan et al., 2002). The G172D substitution was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The G172D variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size and/or other properties. This substitution occurs at a position that is conserved acrossspecies. In silico analysis predicts this variant is probably damaging to the protein structure/function. Amissense variant at the same residue (G172R) and in a nearby residue (T170P) have been reported in theHuman Gene Mutation Database in association with thiamine responsive megaloblastic anemia andthiamine responsive megaloblastic anemia without diabetes, respectively (Stenson et al., 2014), supportingthe functional importance of this region of the protein. We interpret G172D as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000006321 SCV000915365 pathogenic Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness 2018-10-10 criteria provided, single submitter 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.
OMIM RCV000006321 SCV000026503 pathogenic Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness 1999-07-01 no assertion criteria provided literature only

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