Submissions for variant NM_001126108.2(SLC12A3):c.1180+1G>T

gnomAD frequency: 0.00001  dbSNP: rs749098014

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000501643	SCV000598146	pathogenic	Familial hypokalemia-hypomagnesemia	2017-01-16	criteria provided, single submitter	clinical testing	This homozygous variant in SLC12A3 gene was found in a young female patient with Gitelman syndrome
Gharavi Laboratory, Columbia University	RCV000681791	SCV000809255	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000681791	SCV000945150	pathogenic	not provided	2024-11-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the SLC12A3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). This variant is present in population databases (rs749098014, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with Gitelman syndrome (PMID: 14675033, 25422309, 28325561). This variant is also known as "intron 9 +1 G>T". ClinVar contains an entry for this variant (Variation ID: 437426). 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.
Molecular Biology Laboratory, Fundació Puigvert	RCV000501643	SCV001425253	pathogenic	Familial hypokalemia-hypomagnesemia	2020-02-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000501643	SCV001427187	pathogenic	Familial hypokalemia-hypomagnesemia	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gitelman syndrome (MIM#263800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (7 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another canonical splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The c.1180+2T>C variant has been classified as pathogenic by one clinical diagnostic laboratory (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in both homozygous and compound heterozygous individuals with Gitelman syndrome (ClinVar, VCGS, PMIDs: 28325561, 14675033). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000501643	SCV001520560	pathogenic	Familial hypokalemia-hypomagnesemia	2020-01-31	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000501643	SCV001976815	pathogenic	Familial hypokalemia-hypomagnesemia	2021-10-05	criteria provided, single submitter	clinical testing	PVS1, PS3, PM2, PP3, PP5
Genome-Nilou Lab	RCV000501643	SCV002055330	pathogenic	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000501643	SCV002503659	pathogenic	Familial hypokalemia-hypomagnesemia	2021-03-11	criteria provided, single submitter	clinical testing	This sequence change affects the canonical donor splice site in intron 9 of SLC12A3. It is a confirmed spliceogenic variant that causes exon 9 skipping in RNA splicing assays, which is expected to result in nonsense-mediate decay (PS3; PMID: 16221718). Loss of function is a well established mechanism of disease for SLC12A3 (PVS1). The variant is present in a large population cohort at a frequency of 0.003% (rs749098014, 7/248,628 alleles, 0 homozygotes in gnomAD v2.1.1 - PM2), which is consistent with a recessive disorder. It has been identified in the homozygous state or compound heterozygous with another pathogenic allele in at least 15 cases with a clinical diagnosis of Gitelman syndrome (PMID: 14675033, 25422309, 28325561 - PM3_VeryStrong). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PS3, PM2.
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	RCV000501643	SCV002513831	pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PS4, PM1, PM2, PM3, PP3, PP5
Fulgent Genetics, Fulgent Genetics	RCV000501643	SCV002810878	pathogenic	Familial hypokalemia-hypomagnesemia	2021-12-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000681791	SCV003195138	pathogenic	not provided	2023-01-23	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22009145, 20412406, 25841442, 20848653, 26221292, 25422309, 28325561, 21753071, 32742169, 34426522, 31589614, 32939031, 31672324, 30586318, 16221718, 14675033)
Revvity Omics, Revvity	RCV000501643	SCV003827941	pathogenic	Familial hypokalemia-hypomagnesemia	2022-06-30	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000501643	SCV003922322	pathogenic	Familial hypokalemia-hypomagnesemia	2023-05-02	criteria provided, single submitter	curation	The homozygous c.1180+1G>T variant in SLC12A3 was identified by our study in one individual with arthrogryposis multiplex congenita. The c.1180+1G>T variant in SLC12A3 has been reported in 50 unrelated individuals with Gitelman syndrome (PMID: 33532864, PMID: 33532864, PMID: 22009145, PMID: 21415153, SCV001427187.2, SCV000598146.1, PMID: 14675033, PMID: 16221718), segregated with disease in 20 affected relatives from 12 families (PMID: 14675033), but has been identified in 0.004% (5/112998) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs749098014). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 50 affected individuals, 37 were homozygotes (PMID: 33532864, PMID: 22009145, PMID: 21415153, SCV001427187.2, SCV000598146.1, PMID: 14675033, PMID: 16221718), two were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 28325561; PMID: 21415153, ClinVar Variation ID: 1073480), and seven were presumed compound heterozygotes who carried pathogenic or likely pathogenic variants in unknown phase (PMID: 25422309, ClinVar Variation ID: 372504, ClinVar Variation ID: 586604; PMID: 21415153, ClinVar Variation ID: 1071754, ClinVar Variation ID: 974506, ClinVar Variation ID: 8584, ClinVar Variation ID: 437926, ClinVar Variation ID: 8591), which increases the likelihood that the c.1180+1G>T variant in SLC12A3 is pathogenic. This variant has also been reported in ClinVar (Variation ID: 437426) and has been interpreted as pathogenic by multiple submitters. RT-PCR analysis performed on affected tissue shows evidence of exon skipping of exon 9 (PMID: 16221718). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the SLC12A3 gene is an established disease mechanism in Gitelman syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Gitelman syndrome. ACMG/AMP Criteria applied: PVS1, PS3_Moderate, PM2_Supporting, PM3_VeryStrong, PP1_Strong (Richards 2015)
Natera, Inc.	RCV000501643	SCV001458492	pathogenic	Familial hypokalemia-hypomagnesemia	2020-09-16	no assertion criteria provided	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000501643	SCV001468259	pathogenic	Familial hypokalemia-hypomagnesemia	2020-03-26	no assertion criteria provided	clinical testing