rs374163823

Positions:

• chr16-56879593-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001126108.2(SLC12A3):​c.1387G>A​(p.Gly463Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,613,544 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G463E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.37

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 16-56879593-G-A is Pathogenic according to our data. Variant chr16-56879593-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 319903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56879593-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1387G>A	p.Gly463Arg	missense_variant	11/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1387G>A	p.Gly463Arg	missense_variant	11/26		NP_000330.3
SLC12A3	NM_001126107.2	c.1384G>A	p.Gly462Arg	missense_variant	11/26		NP_001119579.2
SLC12A3	NM_001410896.1	c.1384G>A	p.Gly462Arg	missense_variant	11/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1387G>A	p.Gly463Arg	missense_variant	11/26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1387G>A	p.Gly463Arg	missense_variant	11/26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1384G>A	p.Gly462Arg	missense_variant	11/26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1384G>A	p.Gly462Arg	missense_variant	11/26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251074 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461480 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 727082

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152064 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74286

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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,PM5 PP3, PP5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The SLC12A3 c.1387G>A (p.Gly463Arg) missense variant has been reported in three studies in which it is found in two patients with Gitelman syndrome in a compound heterozygous state, one with a second missense variant and one with a deletion variant (Nicolet-Barousse et al. 2005; Vargas-Poussou et al. 2011). Valdez-Flores et al. (2016) report four unrelated families described as carrying the p.Gly463Arg variant. No details of the number of affected individuals or zygosity of the variant are given. Control data are unavailable for the p.Gly463Arg variant which is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated in transfected HEK293 cells that the p.Gly463Arg variant caused significantly lower enzyme activity compared to wild type. Immunoblot assays also showed the p.Gly463Arg variant led to decreased protein expression and abundance in the plasma membrane (Valdez-Flores et al. 2016). Based on the evidence, the p.Gly463Arg variant is classified as likely pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 11, 2024	- -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2020	Published functional studies demonstrate a marked reduction in thiazide-sensitive NaCl cotransporter activity in cells expressing G463R compared to cells expressing wild-type protein (Valdez-Flores et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21415153, 27582097, 31672324, 32140910) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 463 of the SLC12A3 protein (p.Gly463Arg). This variant is present in population databases (rs374163823, gnomAD 0.006%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 15824853, 21415153, 31672324). ClinVar contains an entry for this variant (Variation ID: 319903). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC12A3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 27582097). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.031	D
MutationAssessor	Uncertain	2.8	.;M;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.96
MutPred		0.80		.;Gain of methylation at G463 (P = 0.0199);Gain of methylation at G463 (P = 0.0199);.;
MVP		0.99
MPC		0.51
ClinPred		0.61	D
GERP RS		4.4
Varity_R		0.58
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs374163823; hg19: chr16-56913505; COSMIC: COSV52638970;