Submissions for variant NM_001365088.1(SLC12A6):c.2436+1del (rs515726215)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory,University of Chicago	RCV000499636	SCV000597060	pathogenic	Agenesis of the corpus callosum with peripheral neuropathy	2015-09-18	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000499636	SCV000918210	pathogenic	Agenesis of the corpus callosum with peripheral neuropathy	2018-06-08	criteria provided, single submitter	clinical testing	Variant summary: SLC12A6 c.2436+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site, while three predict the variant weakens a 5' donor site. These predictions are supported by a study that found a cryptic splice site is preferentially used in patient cells and the resulting protein product is reduced in size and does not function in chloride dependent uptake of 86Rb+ compared to controls, although it is properly localized and glycosylated (Howard_2002). The variant allele was found at a frequency of 5.4e-05 in 277348 control chromosomes. This frequency is not higher than expected for a pathogenic variant in SLC12A6 causing Andermann Syndrome (5.4e-05 vs 0.025), allowing no conclusion about variant significance. c.2436+1delG has been reported in the literature in numerous homozygous French Canadian individuals affected with Andermann Syndrome. These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Women's Health, Inc.	RCV000499636	SCV001194234	pathogenic	Agenesis of the corpus callosum with peripheral neuropathy	2019-12-20	criteria provided, single submitter	clinical testing	NM_133647.1(SLC12A6):c.2436+1delG(aka T813fs*813) is classified as pathogenic in the context of Andermann syndrome. Sources cited for classification include the following: PMID 12368912. Classification of NM_133647.1(SLC12A6):c.2436+1delG(aka T813fs*813) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
OMIM	RCV000499636	SCV000025832	pathogenic	Agenesis of the corpus callosum with peripheral neuropathy	2011-08-12	no assertion criteria provided	literature only
GeneReviews	RCV000499636	SCV000166716	pathogenic	Agenesis of the corpus callosum with peripheral neuropathy	2014-06-12	no assertion criteria provided	literature only
Inherited Neuropathy Consortium	RCV000790219	SCV000929611	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only