NM_001126108.2:c.2864G>A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_001126108.2(SLC12A3):c.2864G>A(p.Arg955Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001126108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251492Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135922
GnomAD4 exome AF: 0.000123 AC: 180AN: 1461612Hom.: 0 Cov.: 31 AF XY: 0.000117 AC XY: 85AN XY: 727120
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74368
ClinVar
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Pathogenic:6
The missense variant c.2864G>A(p.Arg955Gln) in SLC12A3 gene has been observed in compound heterozygous state in multiple individuals with Gitelman syndrome (Fujimura et. al., 2018; Ito et. al., 2012). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg955Gln. Experimental studies have shown that this missense change affects SLC12A3 function (De Jong JC et. al., 2002). The observed variant has allele frequency of 0.02% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Arg955Gln in SLC12A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 955 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
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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) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (41 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (12 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SLC12 family domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg955Trp) has been observed in several individuals with Gitelman syndrome (PMIDs: 21415153). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by several clinical laboratories in ClinVar, and has been observed as compound heterozygous in individuals with Gitelman syndrome (LOVD, PMIDs: 21415153, 22214629). This variant has also been previously reported along with two other SLC12A3 variants, p.(Pro643Leu) and p.(Ser28Argfs*19), in one individual with Gitelman syndrome (PMID: 21415153). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:6
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. -
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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. -
SLC12A3: PM3:Very Strong, PM2, PM5, PS3:Supporting, BP4 -
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, 19508680, 30596175, 33348466, 30476936, 35785516, Yanan2023[noPMID], 17654016, 22009145, 35591852) -
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Inborn genetic diseases Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at