Submissions for variant NM_001365088.1(SLC12A6):c.1655G>A (p.Gly552Asp)

dbSNP: rs2140693876

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust	RCV002255113	SCV002037215	likely pathogenic	Peripheral neuropathy	2021-12-18	criteria provided, single submitter	clinical testing	This variant was detected in ten affected individuals from five families. The affected individuals presented with adult onset axonal neuropathy (predominantly sensory). The variant segregated with all affected individuals and was not present among two unaffected individuals. Functional studies of the transporter in Xenopus laevis oocytes and measured K+ influx showed that this variant completely abrogate cotransporter function. The variant has no frequency in population databases and is conserved in paralogue and orthologue domains.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868896	SCV002297922	pathogenic	not provided	2024-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 552 of the SLC12A6 protein (p.Gly552Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with sensory-motor axonal neuropathy (PMID: 36542484). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1328560). 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 SLC12A6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC12A6 function (PMID: 36542484). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004801051	SCV005422967	pathogenic	Charcot-Marie-Tooth disease, axonal, IIa 2II	2024-10-08	criteria provided, single submitter	clinical testing	Variant summary: SLC12A6 c.1655G>A (p.Gly552Asp) results in a non-conservative amino acid change located in the Amino acid permease/ SLC12A domain (IPR004841) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251224 control chromosomes. c.1655G>A has been reported in the literature in multiple heterozygous individuals affected with Charcot-Marie Disease, Axonal, IIa 2II (Loseth_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significantly reduced cotransporter activity in Xenopus oocytes (Loseth_2023). The following publication has been ascertained in the context of this evaluation (PMID: 36542484). ClinVar contains an entry for this variant (Variation ID: 1328560). Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001868896	SCV005875575	pathogenic	not provided	2024-06-06	criteria provided, single submitter	clinical testing	The SLC12A6 c.1655G>A; p.Gly552Asp variant (rs2140693876, ClinVar Variation ID: 1328560) is reported heterozygous in the literature in multiple individuals affected with late-onset sensory-motor axonal neuropathy (Loseth 2023). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional analyses of the variant protein show significant reduction in potassium influx (Loseth 2023). Computational analyses predict that this variant is deleterious (REVEL: 0.976). Based on available information, this variant is considered to be pathogenic. References: Loseth S et al. Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype. Brain. 2023 Mar 1;146(3):912-922. PMID: 36542484.