rs34803727

chr16-56913277-G-Achr16-56913277-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_001126108.2(SLC12A3):c.2938G>A(p.Gly980Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G980W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 4.79

Genes affected

SLC12A3 (HGNC:10912): (solute carrier family 12 member 3) This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56913277-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2780349.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 16-56913277-G-A is Pathogenic according to our data. Variant chr16-56913277-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 586605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56913277-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.2938G>A	p.Gly980Arg	missense_variant	26/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.2965G>A	p.Gly989Arg	missense_variant	26/26
SLC12A3	NM_001126107.2	c.2962G>A	p.Gly988Arg	missense_variant	26/26
SLC12A3	NM_001410896.1	c.2935G>A	p.Gly979Arg	missense_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2938G>A	p.Gly980Arg	missense_variant	26/26	1	NM_001126108.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000558 AC: 14 AN: 251000 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000159 AC: 232 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000203

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	Apr 27, 2022	ACMG criteria used:PS3, PS4, PM1, PM2, PM3, PP1, PP5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 11, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2022	In vitro functional analysis demonstrated significantly diminished metolazone-sensitive sodium uptake levels in cells harboring this variant; immunocytochemical analysis revealed that the altered protein was localized to the cytoplasm and plasma membrane rather than only the plasma membrane as observed with the wild-type protein (De Jong et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as p.(G980R); This variant is associated with the following publications: (PMID: 23328711, 21415153, 11168953, 22009145, 31672324, 33144682, 17329572, 29942493, 18391953, 12039972) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 989 of the SLC12A3 protein (p.Gly989Arg). This variant is present in population databases (rs34803727, gnomAD 0.01%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 17329572, 18391953, 21415153, 23328711, 29942493). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2938G>A (G980R). ClinVar contains an entry for this variant (Variation ID: 586605). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC12A3 protein function. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 12039972). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2020

The c.2965G>A (p.G989R) alteration is located in exon 26 (coding exon 26) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 2965, causing the glycine (G) at amino acid position 989 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the SLC12A3 c.2965G>A alteration was observed in 0.006% (17/282,386) of total alleles studied, with a frequency of 0.01% (14/128,704) in the European (non-Finnish) subpopulation. This alteration has been reported in multiple patients with Gitelman syndrome in both the homozygous and compound heterozygous states (Berry, 2013; Glaudemans, 2012; Vargas-Poussou, 2011; Ji, 2008). This amino acid position is not well conserved in available vertebrate species. In an assay of metolazone-sensitive sodium uptake this variant was found to be functionally abnormal (de Jong, 2002). The in silico prediction for the p.G989R alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Bartter syndrome;C0268450:Familial hypokalemia-hypomagnesemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Jul 13, 2018

This individual is heterozygous for the c.2965G>A variant in the SLC12A3 gene. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.006% (16 out of 276,718 alleles). The c.2965G>A p.(Gly989Arg) variant, which is equivalent to c.2938G>A p.(Gly980Arg) using transcript NM_001126108.1, has been described in many patients with Gitelman syndrome as compound heterozygous with a second pathogenic variant (e.g. De Jong et al. 2002 J Am Soc Nephrol 13: 1442-1448; Riveira-Munoz et al. 2007 J Am Soc Nephrol 18: 1271-1283; Ji et al. 2008 Nat Genet 40: 592-599). Functional studies found that the mutant protein had impaired sodium ion uptake and was also partially incorrectly localised in the cytoplasm (De Jong et al. 2002 J Am Soc Nephrol 13: 1442-1448). This variant is considered to be pathogenic according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N;N;N;N
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Uncertain	0.026	D;D;D;D
Polyphen		0.94	P;D;D;.
Vest4		0.67
MutPred		0.81		.;.;Gain of MoRF binding (P = 0.0334);.;
MVP		0.92
MPC		0.46
ClinPred		0.32	T
GERP RS		4.3
Varity_R		0.63
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs34803727; hg19: chr16-56947189;