rs121909385

Positions:

• chr16-56885307-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001126108.2(SLC12A3):​c.1868T>C​(p.Leu623Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000855 in 1,403,690 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L623L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.91

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 14 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, 2 uncertain in NM_001126108.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 16-56885307-T-C is Pathogenic according to our data. Variant chr16-56885307-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 8595.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.1868T>C	p.Leu623Pro	missense_variant	15/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1868T>C	p.Leu623Pro	missense_variant	15/26
SLC12A3	NM_001126107.2	c.1865T>C	p.Leu622Pro	missense_variant	15/26
SLC12A3	NM_001410896.1	c.1865T>C	p.Leu622Pro	missense_variant	15/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1868T>C	p.Leu623Pro	missense_variant	15/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1868T>C	p.Leu623Pro	missense_variant	15/26	1		A1
SLC12A3	ENST00000566786.5	c.1865T>C	p.Leu622Pro	missense_variant	15/26	1		P4
SLC12A3	ENST00000262502.5	c.1865T>C	p.Leu622Pro	missense_variant	15/26	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000613 AC: 1 AN: 163202 Hom.: 0 AF XY: 0.0000116 AC XY: 1 AN XY: 86188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000833

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000855 AC: 12 AN: 1403690 Hom.: 0 Cov.: 30 AF XY: 0.0000101 AC XY: 7 AN XY: 692816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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	Revvity Omics, Revvity	Jan 26, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2023	Variant summary: SLC12A3 c.1868T>C (p.Leu623Pro) results in a non-conservative amino acid change located in the Amino acid permease/ SLC12A domain (IPR004841) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-06 in 163202 control chromosomes (gnomAD). c.1868T>C has been reported in the literature in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia with evidence of cosegregation with disease (Takeuchi_1996, Riveira-Munoz_2007, Mori_2021), and some patients were reported as compound heterozygous with other (likely) pathogenic or truncating variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8954067, 17329572, 33348466). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2023

For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC12A3 protein function. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 623 of the SLC12A3 protein (p.Leu623Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8954067, 12008755, 17044667, 17329572, 30596175). 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: 8595). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	.;.;D;D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.2	.;M;M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.080	B;B;B;.
Vest4		0.91
MutPred		0.83		.;Loss of stability (P = 0.0039);Loss of stability (P = 0.0039);.;
MVP		0.98
MPC		0.32
ClinPred		0.69	D
GERP RS		5.4
Varity_R		0.69
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121909385; hg19: chr16-56919219;