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| Early onset or syndromic epilepsy v9.84 | ATP6V1A |
Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are more than 30 individuals reported in literature with heterozygous de novo missense variants in ATP6V1A and a Developmental and epileptic encephalopathy (including early onset seizures in at least 28 cases). There are also 6 probands reported with biallelic ATP6V1A variants, of which only 2 presented with seizures. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. As this is a demotion of the BIALLELIC MOI, an expert_review tag was also added.; to: Comment on mode of inheritance: There are more than 30 individuals reported in literature with heterozygous de novo missense variants in ATP6V1A and a Developmental and epileptic encephalopathy (including early onset seizures in at least 28 cases). There are also 6 probands reported with biallelic ATP6V1A variants, of which only 2 presented with seizures. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. |
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| Early onset or syndromic epilepsy v9.84 | ATP6V1A |
Ida Ertmanska Tag Q3_26_demote_amber was removed from gene: ATP6V1A. Tag Q3_26_expert_review was removed from gene: ATP6V1A. Tag Q3_26_MOI tag was added to gene: ATP6V1A. |
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| Early onset or syndromic epilepsy v9.78 | ATP6V1A |
Ida Ertmanska commented on gene: ATP6V1A: Comment on mode of inheritance: There are more than 30 individuals reported in literature with heterozygous de novo missense variants in ATP6V1A and a Developmental and epileptic encephalopathy (including early onset seizures in at least 28 cases). There are also 6 probands reported with biallelic ATP6V1A variants, of which only 2 presented with seizures. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. As this is a demotion of the BIALLELIC MOI, an expert_review tag was also added. |
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| Early onset or syndromic epilepsy v9.78 | ATP6V1A | Ida Ertmanska Phenotypes for gene: ATP6V1A were changed from Epileptic encephalopathy, infantile or early childhood, 3 618012; Cutis laxa, autosomal recessive, type IID 617403 to Developmental and epileptic encephalopathy 93, OMIM:618012; developmental and epileptic encephalopathy 93, MONDO:0020632 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.77 | ATP6V1A | Ida Ertmanska edited their review of gene: ATP6V1A: Changed phenotypes to: Developmental and epileptic encephalopathy 93, OMIM:618012, developmental and epileptic encephalopathy 93, MONDO:0020632 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.77 | ATP6V1A | Ida Ertmanska Publications for gene: ATP6V1A were set to 29668857; 28065471 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | ATP6V1A |
Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: ATP6V1A. Tag Q3_26_expert_review tag was added to gene: ATP6V1A. |
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| Early onset or syndromic epilepsy v9.76 | ATP6V1A |
Ida Ertmanska changed review comment from: BIALLELIC CASES: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys). PMID: 28065471 Van Damme et al., 2017 Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys. Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum). MONOALLELIC CASES: PMID: 40225911 Ma et al., 2024 Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu). Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient. ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026).; to: BIALLELIC CASES: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys). PMID: 28065471 Van Damme et al., 2017 Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys. Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum). All parents reported to be unaffected. MONOALLELIC CASES: PMID: 40225911 Ma et al., 2024 Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu). Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient. ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026). |
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| Early onset or syndromic epilepsy v9.76 | ATP6V1A | Ida Ertmanska edited their review of gene: ATP6V1A: Changed publications to: 28065471, 33320377, 40225911 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | ATP6V1A |
Ida Ertmanska changed review comment from: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).; to: BIALLELIC CASES: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys). PMID: 28065471 Van Damme et al., 2017 Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys. Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum). MONOALLELIC CASES: PMID: 40225911 Ma et al., 2024 Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu). Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient. ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026). |
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| Early onset or syndromic epilepsy v9.76 | ATP6V1A | Ida Ertmanska reviewed gene: ATP6V1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33320377; Phenotypes: Cutis laxa, autosomal recessive, type IID, OMIM:617403, autosomal recessive cutis laxa type 2D, MONDO:0027451; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.191 | ATP6V1A | Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP6V1A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.190 | ATP6V1A | Rebecca Foulger Source NHS GMS was added to ATP6V1A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.189 | ATP6V1A | Rebecca Foulger reviewed gene: ATP6V1A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.188 | ATP6V1A | Tracy Lester reviewed gene: ATP6V1A: Rating: GREEN; Mode of pathogenicity: ; Publications: 29668857; Phenotypes: Cutis laxa, type IID, 617403, Epileptic encephalopathy, infantile or early childhood, 618012; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.917 | ATP6V1A | Sarah Leigh Marked gene: ATP6V1A as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.917 | ATP6V1A | Sarah Leigh Added comment: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.917 | ATP6V1A | Sarah Leigh Gene: atp6v1a has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.917 | ATP6V1A | Sarah Leigh Added comment: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.917 | ATP6V1A | Sarah Leigh Phenotypes for gene: ATP6V1A were changed from # 618012 EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3 - IECEE3; # 617403 CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IID - ARCL2D to Epileptic encephalopathy, infantile or early childhood, 3 618012; Cutis laxa, autosomal recessive, type IID 617403 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.916 | ATP6V1A | Sarah Leigh Classified gene: ATP6V1A as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.916 | ATP6V1A | Sarah Leigh Gene: atp6v1a has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.914 | ATP6V1A |
Konstantinos Varvagiannis gene: ATP6V1A was added gene: ATP6V1A was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Mode of inheritance for gene: ATP6V1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal 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; # 617403 CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IID - ARCL2D Penetrance for gene: ATP6V1A were set to unknown Review for gene: ATP6V1A was set to GREEN Added comment: Heterozygous mutations in ATP6V1A cause Epileptic encephalopathy, infantile or early childhood, type 3 (MIM 618012). PMID: 29668857 reports 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. Sources: Literature, Expert Review |
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