rs200697179

chr16-56885363-C-Gchr16-56885363-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_001126108.2(SLC12A3):c.1924C>G(p.Arg642Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000433 in 1,546,070 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R642C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense, splice_region
• Scores: Splicing: ADA: 0.9764
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.51

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56885363-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 944812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 16-56885363-C-G is Pathogenic according to our data. Variant chr16-56885363-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 397523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56885363-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1924C>G	p.Arg642Gly	missense_variant, splice_region_variant	15/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1924C>G	p.Arg642Gly	missense_variant, splice_region_variant	15/26
SLC12A3	NM_001126107.2	c.1921C>G	p.Arg641Gly	missense_variant, splice_region_variant	15/26
SLC12A3	NM_001410896.1	c.1921C>G	p.Arg641Gly	missense_variant, splice_region_variant	15/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1924C>G	p.Arg642Gly	missense_variant, splice_region_variant	15/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1924C>G	p.Arg642Gly	missense_variant, splice_region_variant	15/26	1		A1
SLC12A3	ENST00000566786.5	c.1921C>G	p.Arg641Gly	missense_variant, splice_region_variant	15/26	1		P4
SLC12A3	ENST00000262502.5	c.1921C>G	p.Arg641Gly	missense_variant, splice_region_variant	15/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0154

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: 0.0000252 AC: 4 AN: 158898 Hom.: 0 AF XY: 0.0000239 AC XY: 2 AN XY: 83662

Gnomad AFR exome AF: 0.00

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: 0.0000644

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000359 AC: 50 AN: 1393890 Hom.: 0 Cov.: 29 AF XY: 0.0000378 AC XY: 26 AN XY: 688230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000447

Gnomad4 OTH exome AF: 0.0000346

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74338

Gnomad4 AFR AF: 0.00

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: 0.0000444 Hom.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000969 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:6

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:PS4, PM1, PM2, PM3, PM5, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Dec 15, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 03, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R642G in SLC12A3 (NM_000339.3) has been previously reported in affected patients (Syren ML et al; Corbetta S et al). The variant was submitted to ClinVar as Pathogenic. The p.R642G variant is observed in 4/62,126 (0.0064%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R642G missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 642 of SLC12A3 is conserved in all mammalian species. The nucleotide c.1924 in SLC12A3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. In the absence of functional studies this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 22, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 642 of the SLC12A3 protein (p.Arg642Gly). This variant is present in population databases (rs200697179, gnomAD 0.007%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 11408395, 12112667, 25422309). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 397523). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12112667, 31028937, 22009145, 11168953, 20675610, 25422309, 11408395, 32397528, 33542107, 34604727, 34768847, 35894287, 36302598, 34532947, 34373523, 35785516) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.8	D;D;D;D
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.96
MutPred		0.81		.;Gain of ubiquitination at K639 (P = 0.0635);Gain of ubiquitination at K639 (P = 0.0635);.;
MVP		0.99
MPC		0.54
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.91
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.83
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: rs200697179; hg19: chr16-56919275;