rs765990518
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_144585.4(SLC22A12):c.1145A>T(p.Gln382Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,611,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_144585.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000463 AC: 7AN: 151122Hom.: 0 Cov.: 26
GnomAD3 exomes AF: 0.000116 AC: 29AN: 250488Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135756
GnomAD4 exome AF: 0.0000288 AC: 42AN: 1460812Hom.: 0 Cov.: 37 AF XY: 0.0000234 AC XY: 17AN XY: 726738
GnomAD4 genome AF: 0.0000463 AC: 7AN: 151122Hom.: 0 Cov.: 26 AF XY: 0.0000542 AC XY: 4AN XY: 73734
ClinVar
Submissions by phenotype
Dalmatian hypouricemia Pathogenic:4
- -
- -
The SLC22A12 c.1145A>T (p.Gln382Leu) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two individuals with renal hypouricemia, and in a heterozygous state in three unaffected family members (Ichida et al. 2004; Wakida et al. 2005). The p.Gln382Leu variant was absent from 75 controls and is reported at a frequency of 0.00093 in the East Asian population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes demonstrated that the p.Gln382Leu variant significantly decreased urate transport compared to wild type SLC22A12 (Ichida et al. 2004; Wakida et al. 2005). Based on the evidence, the p.Gln382Leu variant is classified as likely pathogenic for renal hypouricemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
PM3_Strong+PP4+PS3_Supporting -
SLC22A12-related disorder Pathogenic:1
The SLC22A12 c.1145A>T variant is predicted to result in the amino acid substitution p.Gln382Leu. This variant was reported to be causative for renal hypouricemia (Ichida et al. 2004. PubMed ID: 14694169; Lam et al. 2008. PubMed ID: 18760270; Zhou et al. 2019. PubMed ID: 31131560). Functional studies showed that this variant impairs the transport efficiency (Ichida et al. 2004. PubMed ID: 14694169; Toyoda et al. 2021. PubMed ID: 33821957). This variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-64367222-A-T). This variant is interpreted as likely pathogenic. -
not provided Pathogenic:1
This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 382 of the SLC22A12 protein (p.Gln382Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypouricemia (PMID: 14694169, 15634722, 30097038, 31131560, 31591475). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 305239). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC22A12 function (PMID: 14694169, 15634722). For these reasons, this variant has been classified as Pathogenic. -
Familial renal hypouricemia Pathogenic:1
Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PP4, PS3_Supporting. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at