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

dbSNP: rs515726215

Total submissions: 12

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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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 Genetics, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001357809	SCV001585649	pathogenic	not provided	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (Splice site) in the SLC12A6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A6 are known to be pathogenic (PMID: 12368912, 16606917). This variant is present in population databases (rs752155285, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with agenesis of the corpus callosum with peripheral neuropathy (PMID: 12368912, 12838516, 17893295). It is commonly reported in individuals of French Canadian ancestry (PMID: 12368912). This variant is also known as c.2436+1del. ClinVar contains an entry for this variant (Variation ID: 436730). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000499636	SCV002055412	pathogenic	Agenesis of the corpus callosum with peripheral neuropathy	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001357809	SCV002102613	pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect resulting in nonfunctional protein (Howard et al., 2002); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20301546, 12368912)
Baylor Genetics	RCV000499636	SCV004201150	pathogenic	Agenesis of the corpus callosum with peripheral neuropathy	2024-03-25	criteria provided, single submitter	clinical testing
OMIM	RCV000499636	SCV000025832	pathogenic	Agenesis of the corpus callosum with peripheral neuropathy	2011-08-12	no assertion criteria provided	literature only
GeneReviews	RCV000499636	SCV000166716	not provided	Agenesis of the corpus callosum with peripheral neuropathy		no assertion provided	literature only
Inherited Neuropathy Consortium	RCV000790219	SCV000929611	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357809	SCV001553393	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752923	SCV005361796	pathogenic	SLC12A6-related disorder	2024-04-10	no assertion criteria provided	clinical testing	The SLC12A6 c.2436+1delG variant is predicted to result in a deletion affecting a canonical splice site. In the homozygous state, this variant has been documented to be causative for peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN); and was determined to be a founder mutation in the French Canadian population (Howard et al. 2002. PubMed ID: 12368912, referred to as 2436delG). In vitro functional studies by the same group confirmed the deleterious effect of this variant on splicing. This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.