16-56870119-C-T

Position:

• chr16-56870119-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000563236.6(SLC12A3):​c.625C>T​(p.Arg209Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,470 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R209P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SLC12A3 ENST00000563236.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.64

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in ENST00000563236.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56870120-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1505020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 16-56870119-C-T is Pathogenic according to our data. Variant chr16-56870119-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870119-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.625C>T	p.Arg209Trp	missense_variant	5/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.625C>T	p.Arg209Trp	missense_variant	5/26		NP_000330.3
SLC12A3	NM_001126107.2	c.622C>T	p.Arg208Trp	missense_variant	5/26		NP_001119579.2
SLC12A3	NM_001410896.1	c.622C>T	p.Arg208Trp	missense_variant	5/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.625C>T	p.Arg209Trp	missense_variant	5/26	1	NM_001126108.2	ENSP00000456149	A1
SLC12A3	ENST00000438926.6	c.625C>T	p.Arg209Trp	missense_variant	5/26	1		ENSP00000402152	A1
SLC12A3	ENST00000566786.5	c.622C>T	p.Arg208Trp	missense_variant	5/26	1		ENSP00000457552	P4
SLC12A3	ENST00000262502.5	c.622C>T	p.Arg208Trp	missense_variant	5/26	5		ENSP00000262502	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251174 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135778

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461470 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:3

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 PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 11, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 05, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg209 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11168953, 21415153, 23328711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 10516289). 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. ClinVar contains an entry for this variant (Variation ID: 8586). This missense change has been observed in individual(s) with clinical features of Gitelman syndrome (PMID: 8528245, 31672324). 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. This variant is present in population databases (rs28936388, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 209 of the SLC12A3 protein (p.Arg209Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;D;D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.40	N
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	4.4	.;H;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.5	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.98
MutPred		0.84		.;Loss of disorder (P = 0.0334);Loss of disorder (P = 0.0334);.;
MVP		0.99
MPC		0.48
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.88
gMVP		0.99

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: rs28936388; hg19: chr16-56904031;