Mendeliome
Gene: ATP11A Green List (high evidence)I don't know
PMID: 36300302:
- A family with non-syndromic autosomal-dominant auditory neuropathy/auditory synaptopathy. The same family previously published in PMID: 28601886 Lang-Rogh 2017.
- 5500 bp deletion involving the last coding exon of both RefSeq annotated ATP11A isoforms.
- Present in 10 affected individuals from a multi-generational family, absent in 2 unaffected family members tested.
- RNA studies showed ATP11A deletion allele did not undergo NMD, and led to an inclusion of a pseudoexon of 117 bp size, resulting in a novel 38 amino-acid spanning C-terminus of the mutant protein.
- Mutant ATP11A had normal subcellular localisation.
- Studies in mice showed ATP11A protein is expressed in mouse inner ear, conditional Atp11a ko mice showed age-progressive dysfunction or loss of spiral ganglion neurons.Created: 3 Nov 2022, 3:58 a.m. | Last Modified: 3 Nov 2022, 3:58 a.m.
Panel Version: 1.445
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Deafness, autosomal dominant 84 (MIM#619810)
Publications
Variants in this GENE are reported as part of current diagnostic practice
Green List (high evidence)
PMID 35278131 reports three additional families with deafness, including segregation in a large pedigree.Created: 26 May 2023, 12:30 a.m. | Last Modified: 26 May 2023, 12:30 a.m.
Panel Version: 1.891
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Leukodystrophy, hypomyelinating, 24 , MIM# 619851; Deafness, autosomal dominant 84 (MIM#619810)
Publications
I don't know
Three families described with autosomal dominant non-syndromic deafness:
A Canadian family of European ancestry was described with a novel variant affecting splicing of the 3'UTR of one isoform of ATP11A. RNA studies showed the retention of 153bp of intronic sequence in the 3'UTR. Other isoforms may be variably affected. The variant is deep intronic in the two RefSeq transcripts. Variant was present in 17 affected and absent in 19 unaffected individuals.
Two Jewish Israeli families, one originating from Uzbekistan and one from Afghanistan, described with the same splice variant. RNA studies confirmed extension of the penultimate exon and a PTC (not NMD predicted). Variant segregated in 8 affected individuals, absent from 3 tested unaffected individuals.Created: 7 Apr 2022, 1:47 a.m. | Last Modified: 7 Apr 2022, 1:47 a.m.
Panel Version: 0.12726
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Deafness, autosomal dominant 84 MIM#619810
Publications
Variants in this GENE are reported as part of current diagnostic practice
I don't know
PMID: 34403372:
- Single de novo missense variant reported in a patient with developmental delay and neurological deterioration.
- Patient MRI showed severe cerebral atrophy, ventriculomegaly, hypomyelination leukodystrophy, thinned corpus callosum. Axonal neuropathy suggested.
- K/I heterozygous mice died perinatally.
- Functional studies on missense variant show plasma membrane lipid content impairment, reduced ATPase activity etc.
gnomAD: some NMD PTCs present, good quality variants found with 4-5 hets.
Sources: LiteratureCreated: 4 Oct 2021, 4:25 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Neurological disorder
Publications
Mode of pathogenicity
Other
Gene: atp11a has been classified as Green List (High Evidence).
Publications for gene: ATP11A were set to PMID: 34403372; 35278131
Phenotypes for gene: ATP11A were changed from Neurological disorder; Deafness, autosomal dominant 84 MIM#619810 to Leukodystrophy, hypomyelinating, 24 , MIM# 619851Deafness, autosomal dominant 84 MIM#619810
Phenotypes for gene: ATP11A were changed from Neurological disorder to Neurological disorder; Deafness, autosomal dominant 84 MIM#619810
Publications for gene: ATP11A were set to PMID: 34403372
Mode of inheritance for gene: ATP11A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: atp11a has been classified as Amber List (Moderate Evidence).
Gene: atp11a has been classified as Amber List (Moderate Evidence).
gene: ATP11A was added gene: ATP11A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATP11A were set to PMID: 34403372 Phenotypes for gene: ATP11A were set to Neurological disorder Mode of pathogenicity for gene: ATP11A was set to Other Review for gene: ATP11A was set to AMBER
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 panelapp@genomicsengland.co.uk
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.