Submissions for variant NM_001126108.2(SLC12A3):c.1636A>G (p.Ser546Gly)

dbSNP: rs1451284628

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001880185	SCV002244772	pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: 988170). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 28125972). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 546 of the SLC12A3 protein (p.Ser546Gly).
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328166	SCV001449425	likely pathogenic	Familial hypokalemia-hypomagnesemia; Bartter syndrome	2019-01-25	no assertion criteria provided	clinical testing	This patient is also heterozygous for a variant in SLC12A3, c.1636A>G. , which results in the amino acid substitution of serine to glycine at residue 546, p.(Ser546Gly). The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). p.Ser546Gly has been previously reported in a patient with Gitelman'ss syndrome, in compound heterozygosity with a second variant (Vargas-Poussou et al 2011 J Am Soc Nephrol 22:693-703). It has also been reported by van der Merwe et al 2017 (BMC Nephrology 18:38) in a family with Gitelman'ss syndrome also as compound heterozygous variant in trans with a second variant. The authors showed the variants segregated with disease in 4 affected and 1 unaffected individuals. In silico analysis of pathogenicity (through Alamut Visual v2.7.2) is inconclusive regarding this change; PolyPhen2 and SIFT predicts it to be likely benign whereas MutationTaster predicts this variant to be likely pathogenic. This variant is considered to be likely pathogenic according to the ACMG guidelines (evidence used PM2, PM3, PP1_moderate) .