16-56885283-C-G

Variant names:

• chr16-56885283-C-G
• rs779160677
• NM_001126108.2:c.1844C>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001126108.2(SLC12A3):​c.1844C>G​(p.Ser615Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,400,880 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. S615L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.81
• Publications: 14 publications found

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]

SLC12A3 Gene-Disease associations (from GenCC):

• Gitelman syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001126108.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56885283-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 562346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 138 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -0.93606 (below the threshold of 3.09). Trascript score misZ: 0.71313 (below the threshold of 3.09). GenCC associations: The gene is linked to Gitelman syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 16-56885283-C-G is Pathogenic according to our data. Variant chr16-56885283-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1330263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	NM_001126108.2	MANE Select	c.1844C>G	p.Ser615Trp	missense	Exon 15 of 26	NP_001119580.2
	SLC12A3	NM_000339.3		c.1844C>G	p.Ser615Trp	missense	Exon 15 of 26	NP_000330.3
	SLC12A3	NM_001126107.2		c.1841C>G	p.Ser614Trp	missense	Exon 15 of 26	NP_001119579.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.1844C>G	p.Ser615Trp	missense	Exon 15 of 26	ENSP00000456149.2
	SLC12A3	ENST00000438926.6	TSL:1	c.1844C>G	p.Ser615Trp	missense	Exon 15 of 26	ENSP00000402152.2
	SLC12A3	ENST00000566786.5	TSL:1	c.1841C>G	p.Ser614Trp	missense	Exon 15 of 26	ENSP00000457552.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1400880 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 691200

African (AFR) AF: 0.00 AC: 0 AN: 31716

American (AMR) AF: 0.00 AC: 0 AN: 35948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35962

South Asian (SAS) AF: 0.00 AC: 0 AN: 79280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1079580

Other (OTH) AF: 0.00 AC: 0 AN: 58096

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:2

May 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 29, 2021

MVZ Martinsried, Medicover Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Apr 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser615 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11168953, 20552229, 22728489, 27303630, 30596175). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 1330263). This missense change has been observed in individual(s) with clinical features of SLC12A3-related conditions (PMID: 12112667). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 615 of the SLC12A3 protein (p.Ser615Trp).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.73		Loss of disorder (P = 0.0028)
MVP		0.99
MPC		0.55
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.88
gMVP		0.97
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs779160677; hg19: chr16-56919195;