Submissions for variant NM_020041.3(SLC2A9):c.646G>A (p.Gly216Arg)

gnomAD frequency: 0.00061  dbSNP: rs561633150

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV002246334	SCV002519371	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355676	SCV001550627	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SLC2A9 p.Gly187Arg variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs561633150) and in control databases in 155 of 282076 chromosomes (2 homozygous) at a frequency of 0.0005495 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 153 of 30614 chromosomes (freq: 0.004998) and Other in 2 of 7202 chromosomes (freq: 0.000278), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and European (non-Finnish) populations. The p.Gly187 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Felix Claverie-Martin Laboratory, Hospital Universitario Nuestra Senora de Candelaria	RCV003325566	SCV004032055	pathogenic	Hypouricemia, renal, 2		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003973215	SCV004795577	pathogenic	SLC2A9-related disorder	2023-11-21	no assertion criteria provided	clinical testing	The SLC2A9 c.646G>A variant is predicted to result in the amino acid substitution p.Gly216Arg. In the homozygous or compound heterozygous state, this variant has been reported to be pathogenic for autosomal recessive renal hypouricaemia due to decreased transport activity (Stiburkova et al. 2012. PubMed ID: 22527535; Jeannin et al. 2014. PubMed ID: 24397858; Ruiz et al. 2018. PubMed ID: 29967582; Maalouli et al. 2021. PubMed ID: 34603806). This variant is reported in 0.50% of alleles in individuals of South Asian descent in gnomAD. Of note, some individuals (such as the affected proband's siblings) with severe hypouricemia have been found to be homozygous for this variant, but clinically unaffected (see for example, Maalouli et al. 2021. PubMed ID: 34603806). This variant is interpreted as pathogenic.