Submissions for variant NM_001365088.1(SLC12A6):c.1012C>T (p.Arg338Cys)

gnomAD frequency: 0.00023  dbSNP: rs77122016

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000395538	SCV000390318	uncertain significance	Agenesis of the corpus callosum with peripheral neuropathy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000879703	SCV001022751	likely benign	not provided	2025-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000879703	SCV001820971	likely benign	not provided	2019-04-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000395538	SCV002055399	likely benign	Agenesis of the corpus callosum with peripheral neuropathy	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238887	SCV005886639	likely benign	not specified	2025-02-04	criteria provided, single submitter	clinical testing	Variant summary: SLC12A6 c.1012C>T (p.Arg338Cys) 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 allele was found at a frequency of 0.00045 in 251422 control chromosomes (including one homozygote), predominantly at a frequency of 0.0028 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in SLC12A6 causing Agenesis of the corpus callosum with peripheral neuropathy phenotype. c.1012C>T has been reported in the literature in the homozygous state in a fetus affected with agenesis of the corpus callosum who underwent prenatal exome sequencing; however the finding was not considered causal and, in a subsequent pregnancy, a similarly affected fetus did not carry the variant (de Koning_2022). This report does not provide unequivocal conclusions about association of the variant with agenesis of the corpus callosum with peripheral neuropathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34611884). ClinVar contains an entry for this variant (Variation ID: 315618). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV000395538	SCV001454679	uncertain significance	Agenesis of the corpus callosum with peripheral neuropathy	2020-04-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003957635	SCV004776311	likely benign	SLC12A6-related disorder	2021-03-31	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).