16-56885363-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>T(p.Arg642Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000556 in 1,546,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R642G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense, splice_region
• Scores: Splicing: ADA: 0.9855
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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-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.
• 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-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1924C>T	p.Arg642Cys	missense_variant, splice_region_variant	15/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1924C>T	p.Arg642Cys	missense_variant, splice_region_variant	15/26
SLC12A3	NM_001126107.2	c.1921C>T	p.Arg641Cys	missense_variant, splice_region_variant	15/26
SLC12A3	NM_001410896.1	c.1921C>T	p.Arg641Cys	missense_variant, splice_region_variant	15/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1924C>T	p.Arg642Cys	missense_variant, splice_region_variant	15/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1924C>T	p.Arg642Cys	missense_variant, splice_region_variant	15/26	1		A1
SLC12A3	ENST00000566786.5	c.1921C>T	p.Arg641Cys	missense_variant, splice_region_variant	15/26	1		P4
SLC12A3	ENST00000262502.5	c.1921C>T	p.Arg641Cys	missense_variant, splice_region_variant	15/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000126 AC: 20 AN: 158898 Hom.: 0 AF XY: 0.0000837 AC XY: 7 AN XY: 83662

Gnomad AFR exome AF: 0.000111

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000694

Gnomad SAS exome AF: 0.000219

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000483

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000560 AC: 78 AN: 1393890 Hom.: 0 Cov.: 29 AF XY: 0.0000509 AC XY: 35 AN XY: 688230

Gnomad4 AFR exome AF: 0.0000634

Gnomad4 AMR exome AF: 0.0000835

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000780

Gnomad4 SAS exome AF: 0.0000884

Gnomad4 FIN exome AF: 0.0000405

Gnomad4 NFE exome AF: 0.0000326

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74466

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ExAC AF: 0.0000388 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.53; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC12A3 related disorder (ClinVar ID: VCV000944812 / PMID: 10561140). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 10561140, 15069170, 16370563). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 15069170). Different missense changes at the same codon (p.Arg642Gly, p.Arg642His) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000319909, VCV000397523). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 02, 2020	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 642 of the SLC12A3 protein (p.Arg642Cys). This variant is present in population databases (rs200697179, gnomAD 0.07%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 10561140, 15069170, 16370563, 21051746). 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 also known as c.1930C>T. ClinVar contains an entry for this variant (Variation ID: 944812). 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. This variant disrupts the p.Arg642 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 12112667), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.7	D;D;D;D
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.95
MVP		0.99
MPC		0.55
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.84
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
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; COSMIC: COSV52635909;