ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.2864G>A (p.Arg955Gln)

gnomAD frequency: 0.00008  dbSNP: rs202114767
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV000477802 SCV000893418 pathogenic Familial hypokalemia-hypomagnesemia 2022-05-10 criteria provided, single submitter clinical testing
Invitae RCV000681947 SCV000932032 pathogenic not provided 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 964 of the SLC12A3 protein (p.Arg964Gln). This variant is present in population databases (rs202114767, gnomAD 0.2%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 8528245, 17654016, 21415153, 22214629, 30596175). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg955Gln. ClinVar contains an entry for this variant (Variation ID: 417864). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 12039972). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000681947 SCV001826237 likely pathogenic not provided 2023-05-31 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12039972, 8528245, 21415153, 15206555, 18391953, 31589614, 22214629, 35327948, 17654016, 19508680, 30596175, 33348466, 35785516, Yanan2023[noPMID], 22009145)
Athena Diagnostics Inc RCV000681947 SCV001879514 pathogenic not provided 2020-12-15 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Study showed this variant to significantly reduce sodium uptake compared to wild-type (PMID: 12039972). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Genome-Nilou Lab RCV000477802 SCV002055355 likely pathogenic Familial hypokalemia-hypomagnesemia 2021-07-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002525742 SCV003755755 pathogenic Inborn genetic diseases 2020-11-05 criteria provided, single submitter clinical testing The c.2891G>A (p.R964Q) alteration is located in exon 25 (coding exon 25) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 2891, causing the arginine (R) at amino acid position 964 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD) database, the SLC12A3 c.2891G>A alteration was observed in 0.01% (41/282888) of total alleles studied, with a frequency of 0.17% (18/10370) in the Ashkenazi Jewish subpopulation. This alteration has been reported in multiple patients with Gitelman syndrome in both the homozygous and compound heterozygous states (Enya, 2004; Fava, 2007; Nakamura, 2010; Vargas-Poussou, 2011; Glaudemans, 2012; Ito, 2012; Fujimura, 2019). This amino acid position is well conserved in available vertebrate species. The in silico prediction for the p.R964Q alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000681947 SCV004033492 pathogenic not provided 2023-08-01 criteria provided, single submitter clinical testing SLC12A3: PM3:Very Strong, PM2, PM5, PS3:Supporting, BP4
Revvity Omics, Revvity Omics RCV000477802 SCV004238359 pathogenic Familial hypokalemia-hypomagnesemia 2023-05-19 criteria provided, single submitter clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia RCV000477802 SCV000536717 pathogenic Familial hypokalemia-hypomagnesemia 2015-09-23 no assertion criteria provided research
Gharavi Laboratory, Columbia University RCV000681947 SCV000809435 likely pathogenic not provided 2018-09-16 no assertion criteria provided research

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