rs772429581
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_020041.3(SLC2A9):c.354dupC(p.Ile119HisfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_020041.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251362Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135856
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461864Hom.: 0 Cov.: 57 AF XY: 0.0000289 AC XY: 21AN XY: 727240
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74382
ClinVar
Submissions by phenotype
Hypouricemia, renal, 2 Pathogenic:3Uncertain:1
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The SLC2A9 c.354dupC (p.Ile119HisfsTer27) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Ile119HisfsTer27 variant has been reported in a homozygous state in two siblings with renal hypouricemia (Stiburkova et al. 2011). The variant was absent from 150 controls but is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes demonstrated that the p.Ile119HisfsTer27 variant resulted in a significant decrease in urate uptake compared to wildtype (Mancikova et al. 2015). Due to the potential impact of frameshift variants and the supporting evidence from the literature, the p.Ile119HisfsTer27 variant is classified as a variant of unknown significance but suspicious for pathogenicity for renal hypouricemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Ile119Hisfs*27) in the SLC2A9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC2A9 are known to be pathogenic (PMID: 19926891, 21256783, 21536615, 24628802). This variant is present in population databases (rs772429581, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with clinical features of renal hypouricemia (PMID: 21256783). This variant is also known as p.I118HfsX27. ClinVar contains an entry for this variant (Variation ID: 350238). For these reasons, this variant has been classified as Pathogenic. -
SLC2A9: PM2, PM3, PVS1:Moderate, PS3:Supporting -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at