rs1555499234

chr16-56867069-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001126108.2(SLC12A3):c.283del(p.Gln95ArgfsTer19) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,459,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.80

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 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-56867069-GC-G is Pathogenic according to our data. Variant chr16-56867069-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 448955.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.283del	p.Gln95ArgfsTer19	frameshift_variant, splice_region_variant	2/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.283del	p.Gln95ArgfsTer19	frameshift_variant, splice_region_variant	2/26
SLC12A3	NM_001126107.2	c.283-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SLC12A3	NM_001410896.1	c.283-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.283del	p.Gln95ArgfsTer19	frameshift_variant, splice_region_variant	2/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.283del	p.Gln95ArgfsTer19	frameshift_variant, splice_region_variant	2/26	1		A1
SLC12A3	ENST00000566786.5	c.283-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P4
SLC12A3	ENST00000262502.5	c.283-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459876 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726324

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics UMG, Mater Domini University Hospital/ Magna Graecia University of Catanzaro	Mar 24, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 11, 2023	This variant is also known as Q95fs. ClinVar contains an entry for this variant (Variation ID: 448955). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with Gitelman syndrome (PMID: 17699451, 27872838). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Gln95Argfs*19) in the SLC12A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2019	The c.283delC pathogenic variant in the SLC12A3 gene has been reported previously with another SLC12A3 variant in several individuals with Gitelman syndrome (Colussi et al., 2007; Corbetta et al., 2015; Grillone et al., 2016). The c.283delC variant causes a frameshift starting with codon Glutamine 95, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Gln95ArgfsX19. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.283delC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.283delC as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.93		Position offset: 2
DS_AL_spliceai		0.93		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555499234; hg19: chr16-56900981;