DDG2P
Gene: SLC12A6 Green List (high evidence)Green List (high evidence)
The DDG2P confidence category for the disease AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY, OMIM:218000 is definitive. The allelic requirement and mutation consequence are biallelic_autosomal and absent gene product (PMIDs: 12368912;17893295;21628467;16606917).Created: 4 Oct 2023, 5:08 p.m. | Last Modified: 4 Oct 2023, 5:08 p.m.
Panel Version: 3.12
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY, OMIM:218000
Publications
For-review tag has been added as it maybe appropriate to change the MOI to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.Created: 13 Jul 2020, 3:33 p.m. | Last Modified: 13 Jul 2020, 3:33 p.m.
Panel Version: 2.9
Associated with Agenesis of the corpus callosum with peripheral neuropathy 218000 in OMIM and as confirmed Gen2Phen gene. At least 10 biallelic variants were reported in at least 10 unrelated cases. 9/10 of these variants was terminating (PMID 12368912, 16606917, 17893295). Three de novo heterozygous missense variants have been identified in four unrelated cases with a milder phenotype of early- onset progressive Charcot- Marie-tooth disease (CMT) with or without spasticity (intermediate CMT)(PMID 31439721, 27485015). The authors of PMID 31439721 suggest that "autosomal- dominant inheritance of SLC12A6 variants also needs to be considered in patients with early- onset neuropathies". Furthermore, it will be important to understand the functional differences between the variants, as PMID 27485015 reported variant - p.Thr991Ala, resulted in increased potassium influx in Xenopus oocytes (gain-of-function), while the other missense variants identified so far had a loss-of-function effect in varying degrees (PMID 31439721).Created: 13 Jul 2020, 3:32 p.m. | Last Modified: 13 Jul 2020, 3:32 p.m.
Panel Version: 2.9
I don't know
Original DDG2P rating: confirmed.Created: 19 Nov 2018, 11:30 a.m.
Publications for gene: SLC12A6 were updated from 12368912; 31439721; 27485015; 16606917; 17893295; 21628467 to 21628467; 12368912; 27485015; 16606917; 17893295; 31439721
Publications for gene: SLC12A6 were set to 17893295; 16606917; 21628467; 12368912
Rebecca Foulger: Original DDG2P rating: confirm
gene: SLC12A6 was added gene: SLC12A6 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype Mode of inheritance for gene: SLC12A6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC12A6 were set to 17893295; 16606917; 21628467; 12368912 Phenotypes for gene: SLC12A6 were set to AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY 218000
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.