NM_144585.4:c.269G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

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 (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

SLC22A12
NM_144585.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.17

Variant links:

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]

SLC22A12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SLC22A12	NM_144585.4 link	c.269G>A	p.Arg90His	missense_variant	Exon 1 of 10	ENST00000377574.6	NP_653186.2	Q96S37-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A12	ENST00000377574.6 link	c.269G>A	p.Arg90His	missense_variant	Exon 1 of 10	1	NM_144585.4	ENSP00000366797.1		Q96S37-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

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:

AN:

246684

Hom.:

AF XY:

0.000224

AC XY:

AN XY:

134192

show subpopulations

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.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

726262

show subpopulations

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:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74468

show subpopulations

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.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dalmatian hypouricemia

Pathogenic:6

Oct 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 21, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs121907896, gnomAD 0.2%). 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. ClinVar contains an entry for this variant (Variation ID: 3516). 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: 33821957). For these reasons, this variant has been classified as Pathogenic. -

Familial renal hypouricemia

Pathogenic:1

Sep 21, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

.;D;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

3.1

M;M;M;M

PrimateAI

Benign

0.37

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over