rs752101663

chr16-56887937-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001126108.2(SLC12A3):c.2191G>A(p.Gly731Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,612,116 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. G731W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.76

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56887937-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1957657.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 16-56887937-G-A is Pathogenic according to our data. Variant chr16-56887937-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.2191G>A	p.Gly731Arg	missense_variant	18/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.2191G>A	p.Gly731Arg	missense_variant	18/26
SLC12A3	NM_001126107.2	c.2188G>A	p.Gly730Arg	missense_variant	18/26
SLC12A3	NM_001410896.1	c.2188G>A	p.Gly730Arg	missense_variant	18/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2191G>A	p.Gly731Arg	missense_variant	18/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.2191G>A	p.Gly731Arg	missense_variant	18/26	1		A1
SLC12A3	ENST00000566786.5	c.2188G>A	p.Gly730Arg	missense_variant	18/26	1		P4
SLC12A3	ENST00000262502.5	c.2188G>A	p.Gly730Arg	missense_variant	18/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.0000462 AC: 7 AN: 151414 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000729

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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251158 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135854

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

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: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1460702 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 726692

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

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: 0.0000126

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000462 AC: 7 AN: 151414 Hom.: 0 Cov.: 30 AF XY: 0.0000271 AC XY: 2 AN XY: 73922

Gnomad4 AFR AF: 0.0000729

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: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:5

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, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Apr 13, 2020	The c.2191G>A variant in the SLC12A3 gene is a heterozygous missense variant, which results in the substitution of the highly conserved glycine residue at the 731 position to arginine (p.Gly731Arg). This variant localizes to coding exon 18 of the SLC12A3 gene (26 exons total; NM_000339.3). This variant is predicted to be deleterious and damaging to protein structure and/or function based on in silico analyses (PROVEAN and SIFT). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (allele frequency = 0.00002837, no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in multiple individuals with Gitelman syndrome either in the homozygous state or with another SLC12A3 variant (PMIDs: 17699451, 21415153, 30596175, 25422309). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 30, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 731 of the SLC12A3 protein (p.Gly731Arg). This variant is present in population databases (rs752101663, gnomAD 0.004%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8900229, 12112667, 21415153, 25422309). 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: 562347). 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. -
Likely pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.5	D;D;D;D
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.98	D;P;P;.
Vest4		0.98
MutPred		0.92		.;Gain of MoRF binding (P = 0.0195);Gain of MoRF binding (P = 0.0195);.;
MVP		0.98
MPC		0.29
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.87
gMVP		0.94

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: rs752101663; hg19: chr16-56921849;