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Intellectual disability

Gene: ATP6V1A

Green List (high evidence)

ATP6V1A (ATPase H+ transporting V1 subunit A)
EnsemblGeneIds (GRCh38): ENSG00000114573
EnsemblGeneIds (GRCh37): ENSG00000114573
OMIM: 607027, Gene2Phenotype
ATP6V1A is in 5 panels

2 reviews

Louise Daugherty (Genomics England Curator)

Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Created: 19 Nov 2018, 11:32 a.m.
From Sarah Leigh (Genomics England Curator) review 18 Nov 2018, 10:49 p.m Genetic epilepsy syndromes. Panel version: 0.917. Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least 4 variants were identified in unrelated cases of Epileptic encephalopathy, infantile or early childhood, 3 618012, one variant (c.1045G>A, NM_001690.3, p.D349N) appear give gain of function results in in vitro analysis, whereas the others had loss of function. Two homozygous variants were reported in two unrelated cases of Cutis laxa, autosomal recessive, type IID 617403 who both had seizures as part of their phenotypes.
Comment on phenotypes: Monoallelic variants associated with Epileptic encephalopathy, infantile or early childhood, 3 618012 and biallelic variants associated with Cutis laxa, autosomal recessive, type IID 617403. Both phenotypes include seizures.
Created: 19 Nov 2018, 11:06 a.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Heterozygous mutations in ATP6V1A cause Epileptic encephalopathy, infantile or early childhood, type 3 (MIM 618012).

PMID: 29668857 reports on 4 individuals from 4 families with de novo pathogenic variants in ATP6V1A. The phenotype was consistent with a developmental encephalopathy with epilepsy.

All patients were found to harbor missense variants. The variants resulted in altered lysosomal homeostasis, abnormal neuritogenesis and synaptic density. However in one of the variants tested (p.Asp100Tyr) pathogenicity was mediated by loss-of-function mechanism while for another (p.Asp349Asn) by gain-of-function mechanism.

Differences in severity were noted, with two variants (incl. Asp100Tyr) being associated with a more severe phenotype and the two other (incl. Asp349Asn) with milder degrees of ID and epilepsy.

Biallelic ATP6V1A mutations cause Cutis laxa type IID (MIM 617403). PMID: 28065471 is the first report on 3 individuals from 3 different families (2 of which were consanguineous). All patients were homozygous for ATP6V1A pathogenic variants. All three presented with hypotonia, one (or possibly two) with developmental delay and two with seizures although the developmental phenotype is not further commented on. (Additional patients described in the article harbored mutations in other genes and were not considered).

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Created: 17 Nov 2018, 7:49 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
# 618012 EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3; IECEE3

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
Phenotypes
  • Epileptic encephalopathy, infantile or early childhood, 3 618012
  • Cutis laxa, autosomal recessive, type IID 617403
OMIM
607027
Clinvar variants
Variants in ATP6V1A
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

19 Nov 2018, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: atp6v1a has been classified as Green List (High Evidence).

19 Nov 2018, Gel status: 0

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: ATP6V1A were changed from # 618012 EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3; IECEE3 to Epileptic encephalopathy, infantile or early childhood, 3 618012; Cutis laxa, autosomal recessive, type IID 617403

17 Nov 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: ATP6V1A was added gene: ATP6V1A was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: ATP6V1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATP6V1A were set to 29668857; 28065471 Phenotypes for gene: ATP6V1A were set to # 618012 EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3; IECEE3 Penetrance for gene: ATP6V1A were set to unknown Review for gene: ATP6V1A was set to GREEN