rs121907896

chr11-64591825-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_144585.4(SLC22A12):c.269G>A(p.Arg90His) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,612,014 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: SLC22A12 NM_144585.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.17

Genes affected

SLC22A12 (HGNC:17989): (solute carrier family 22 member 12) The protein encoded by this gene is a member of the organic anion transporter (OAT) family, and it acts as a urate transporter to regulate urate levels in blood. This protein is an integral membrane protein primarily found in epithelial cells of the proximal tubule of the kidney. An elevated level of serum urate, hyperuricemia, is associated with increased incidences of gout, and mutations in this gene cause renal hypouricemia type 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64591825-G-A is Pathogenic according to our data. Variant chr11-64591825-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1300683).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A12	NM_144585.4	c.269G>A	p.Arg90His	missense_variant	1/10	ENST00000377574.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A12	ENST00000377574.6	c.269G>A	p.Arg90His	missense_variant	1/10	1	NM_144585.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000178 AC: 44 AN: 246684 Hom.: 0 AF XY: 0.000224 AC XY: 30 AN XY: 134192

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00211

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1459718 Hom.: 1 Cov.: 35 AF XY: 0.000107 AC XY: 78 AN XY: 726262

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00292

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74468

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dalmatian hypouricemia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across several studies, the SLC22A12 c.269G>A (p.Arg90His) missense variant has been reported in at least 18 individuals with renal hypouricemia including two homozygotes, 15 compound heterozygotes, and one heterozygote, who present with phenotypes ranging from no clinical symptoms to acute kidney injury after strenuous exercise (Ichida et al. 2004; Iwai et al. 2004; Ishikawa et al. 2005; Cheong et al. 2005; Komatsuda et al. 2006; Inazu et al. 2007; Ichida et al. 2008; Lee et al. 2008; Ochi et al. 2012). Ishikawa et al. (2005) noted that the p.Arg90His variant segregated with disease in multiple members of a large family. The variant was absent from 192 controls, but is reported at a frequency of 0.00237 in the East Asian population of the Exome Aggregation Consortium. Ichida et al. (2004) demonstrated that urate transport activity for the p.Arg90His variant in Xenopus oocytes was significantly decreased in comparison with that of wild type and was similar to that of oocytes that were not injected with URAT1 cRNA. Ichida et al. (2004) also demonstrated through immunocytochemical analysis that the variant exhibited similar staining patterns to wild type in the plasma membrane of Xenopus oocytes. Based on the collective evidence, the p.Arg90His variant is classified as pathogenic for renal hypouricemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.018%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003516). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 15741204, 16703794, 22045201). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 29, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

This missense change has been observed in individual(s) with renal hypouricemia (PMID: 15741204, 16703794, 18492088, 30097038). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC22A12 function (PMID: 33821957). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 3516). This variant is present in population databases (rs121907896, gnomAD 0.2%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 90 of the SLC22A12 protein (p.Arg90His). -

Familial renal hypouricemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 21, 2018

The p.Arg90His variant in SLC22A12 has been identified in the homozygous or comp ound heterozygous state in at least 10 individuals with hypouricemia, most of wh om had Asian ancestry, (Iwai 2004, Ichida 2004, Komatsuda 2006, Inazu 2007, Lee 2008, Tasic 2011) and segregated with disease in 2 affected members from 1 famil y (Ishikawa 2005). All of these individuals had biochemical features consistent with hypouricemia, but only a subset were clinically affected. In vitro function al studies support an impact to protein function (Ichida 2004). This variant has been identified in 0.2% (37/17126) of East Asian chromosomes by gnomAD (http:// gnomad.broadinstitute.org). This frequency is consistent with the reported reduc ed penetrance for this disorder. In summary, this variant meets criteria to be c lassified as pathogenic for autosomal recessive hereditary renal hypouricemia, w hich has significantly reduced clinical penetrance, based on case observations a nd segregation studies. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	23
Dann	Pathogenic	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.1	M;M;M;M
MutationTaster	Benign	0.54	A;A;A;A;A
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.061	T;D;T;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		0.97	D;D;D;.
Vest4		0.25
MPC		0.96
ClinPred		0.29	T
GERP RS		3.5
Varity_R		0.30
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121907896; hg19: chr11-64359297;