The c.2222G>A (p.R741Q) alteration is located in exon 19 (coding exon 18) of the ATP6V0A1 gene. This alteration results from a G to A substitution at nucleotide position 2222, causing the arginine (R) at amino acid position 741 to be replaced by a glutamine (Q)._x000D_ _x000D_ for autosomal dominant ATP6V0A1-related developmental and epileptic encephalopathy; however, its clinical significance for autosomal recessive ATP6V0A1-related neurodevelopmental disorder is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, also known as c.2219G>A (p.R740Q), was reported de novo in ten patients with developmental and epileptic encephalopathy (Aoto, 2021; Bott, 2021). This amino acid position is highly conserved in available vertebrate species. The R741Q (aka R740Q) variant is located in a critical transmembrane domain that may inhibit glutamate deprotonation. In vitro functional studies of the R740Q variant demonstrated altered organelle acidification and failure of lysosomal hydrolysis impairing canonical proton-pumping V-ATPase function. In addition, homozygote nematodes carrying the corresponding R740Q mutation showed severe developmental arrest at early larval stage (Bott, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001130021.3(ATP6V0A1):c.2219G>A (p.Arg740Gln)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001130021.3(ATP6V0A1):c.2219G>A (p.Arg740Gln)
Variation ID: 560227 Accession: VCV000560227.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.2 17: 42513949 (GRCh38) [ NCBI UCSC ] 17: 40665967 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 8, 2018 Oct 13, 2024 Aug 1, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001130021.3:c.2219G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001123493.1:p.Arg740Gln missense NM_001130020.3:c.2222G>A NP_001123492.1:p.Arg741Gln missense NM_001378522.1:c.2240G>A NP_001365451.1:p.Arg747Gln missense NM_001378523.1:c.2114G>A NP_001365452.1:p.Arg705Gln missense NM_001378530.1:c.2417G>A NP_001365459.1:p.Arg806Gln missense NM_001378531.1:c.2363G>A NP_001365460.1:p.Arg788Gln missense NM_001378532.1:c.2345G>A NP_001365461.1:p.Arg782Gln missense NM_001378533.1:c.2342G>A NP_001365462.1:p.Arg781Gln missense NM_001378534.1:c.2315G>A NP_001365463.1:p.Arg772Gln missense NM_001378535.1:c.2294G>A NP_001365464.1:p.Arg765Gln missense NM_001378536.1:c.2111G>A NP_001365465.1:p.Arg704Gln missense NM_001378537.1:c.2093G>A NP_001365466.1:p.Arg698Gln missense NM_001378538.1:c.2090G>A NP_001365467.1:p.Arg697Gln missense NM_001378539.1:c.2240G>A NP_001365468.1:p.Arg747Gln missense NM_001378540.1:c.2072G>A NP_001365469.1:p.Arg691Gln missense NM_001378541.1:c.2222G>A NP_001365470.1:p.Arg741Gln missense NM_001378542.1:c.2219G>A NP_001365471.1:p.Arg740Gln missense NM_001378543.1:c.2042G>A NP_001365472.1:p.Arg681Gln missense NM_001378544.1:c.2201G>A NP_001365473.1:p.Arg734Gln missense NM_001378545.1:c.2009G>A NP_001365474.1:p.Arg670Gln missense NM_001378546.1:c.2006G>A NP_001365475.1:p.Arg669Gln missense NM_001378547.1:c.1988G>A NP_001365476.1:p.Arg663Gln missense NM_001378548.1:c.1973G>A NP_001365477.1:p.Arg658Gln missense NM_001378549.1:c.2039G>A NP_001365478.1:p.Arg680Gln missense NM_001378550.1:c.2093G>A NP_001365479.1:p.Arg698Gln missense NM_001378551.1:c.2324G>A NP_001365480.1:p.Arg775Gln missense NM_001378552.1:c.2324G>A NP_001365481.1:p.Arg775Gln missense NM_001378553.1:c.2042G>A NP_001365482.1:p.Arg681Gln missense NM_001378554.1:c.1991G>A NP_001365483.1:p.Arg664Gln missense NM_001378555.1:c.1991G>A NP_001365484.1:p.Arg664Gln missense NM_001378556.1:c.2093G>A NP_001365485.1:p.Arg698Gln missense NM_001378557.1:c.2093G>A NP_001365486.1:p.Arg698Gln missense NM_005177.5:c.2201G>A NP_005168.2:p.Arg734Gln missense NC_000017.11:g.42513949G>A NC_000017.10:g.40665967G>A NG_047037.1:g.60106G>A - Protein change
- R741Q, R734Q, R740Q, R658Q, R663Q, R664Q, R669Q, R670Q, R680Q, R681Q, R691Q, R697Q, R698Q, R704Q, R705Q, R747Q, R765Q, R772Q, R775Q, R781Q, R782Q, R788Q, R806Q
- Other names
-
p.Arg741Gln
- Canonical SPDI
- NC_000017.11:42513948:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| ATP6V0A1 | - | - |
GRCh38 GRCh37 |
69 | 78 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Apr 20, 2022 | RCV000678272.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 1, 2022 | RCV001267573.11 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 29, 2022 | RCV002226480.8 | |
| Likely pathogenic (3) |
criteria provided, single submitter
|
Mar 29, 2022 | RCV002271565.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 22, 2022 | RCV002226479.8 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001445755.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.2222G>A (p.R741Q) alteration is located in exon 19 (coding exon 18) of the ATP6V0A1 gene. This alteration results from a G to A substitution … (more)
The c.2222G>A (p.R741Q) alteration is located in exon 19 (coding exon 18) of the ATP6V0A1 gene. This alteration results from a G to A substitution at nucleotide position 2222, causing the arginine (R) at amino acid position 741 to be replaced by a glutamine (Q)._x000D_ _x000D_ for autosomal dominant ATP6V0A1-related developmental and epileptic encephalopathy; however, its clinical significance for autosomal recessive ATP6V0A1-related neurodevelopmental disorder is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, also known as c.2219G>A (p.R740Q), was reported de novo in ten patients with developmental and epileptic encephalopathy (Aoto, 2021; Bott, 2021). This amino acid position is highly conserved in available vertebrate species. The R741Q (aka R740Q) variant is located in a critical transmembrane domain that may inhibit glutamate deprotonation. In vitro functional studies of the R740Q variant demonstrated altered organelle acidification and failure of lysosomal hydrolysis impairing canonical proton-pumping V-ATPase function. In addition, homozygote nematodes carrying the corresponding R740Q mutation showed severe developmental arrest at early larval stage (Bott, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autism
Intellectual disability Cerebellar ataxia Lower limb spasticity Focal-onset seizure Severe global developmental delay
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002505561.1
First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022 |
Comment:
This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PS3_SUP, PM2_SUP, PP2, PP3
|
|
|
Likely pathogenic
(Mar 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Microcephaly
Seizure Hypotonia Global developmental delay Large for gestational age
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002505572.1
First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022 |
Comment:
Criteria applied: PS3_MOD, PS4_MOD, PM2_SUP, PP2, PP3
|
|
|
Pathogenic
(Apr 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003461949.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral … (more)
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 741 of the ATP6V0A1 protein (p.Arg741Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ATP6V0A1-related conditions (PMID: 28135719, 33833240; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 560227). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). (less)
|
|
|
Likely pathogenic
(Mar 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy 104
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005368444.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PS3_MOD,PS4_MOD,PM2_SUP,PP2,PP3
Clinical Features:
Seizure (present) , Large for gestational age (present) , Global developmental delay (present) , Hypotonia (present) , Microcephaly (present)
Sex: male
|
|
|
Pathogenic
(Jul 26, 2022)
|
no assertion criteria provided
Method: literature only
|
DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 104
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV002553198.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment on evidence:
In 2 unrelated patients with developmental and epileptic encephalopathy-104 (DEE104; 619970), Aoto et al. (2021) identified heterozygosity for a c.2222G-A transition (c.2222G-A, NM_001130020.1) in the … (more)
In 2 unrelated patients with developmental and epileptic encephalopathy-104 (DEE104; 619970), Aoto et al. (2021) identified heterozygosity for a c.2222G-A transition (c.2222G-A, NM_001130020.1) in the ATP6V0A gene, resulting in an arg741-to-gln (R741Q) substitution. The mutation was identified by whole-exome sequencing. In patient 1, the mutation was shown to be de novo. In patient 2, the mutation was not present in the mother but was not tested in the father. The variant was not present in the gnomAD database. HEK293FT cells transfected with ATP6V0A containing the R741Q mutation had impaired lysosomal acidification. (less)
|
|
|
Likely pathogenic
(May 28, 2020)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
de novo
|
Molecular Genetics laboratory, Necker Hospital
Accession: SCV004031343.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Clinical Features:
Intellectual disability (present)
|
|
|
Pathogenic
(Oct 04, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Developmental and epileptic encephalopathy 104
Affected status: yes
Allele origin:
de novo
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV004242212.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Number of individuals with the variant: 1
Clinical Features:
Abnormal delivery (present) , Caesarian section (present) , Secondary Caesarian section (present) , Motor stereotypies (present) , Intellectual disability (present) , Seizure (present) , Global … (more)
Abnormal delivery (present) , Caesarian section (present) , Secondary Caesarian section (present) , Motor stereotypies (present) , Intellectual disability (present) , Seizure (present) , Global developmental delay (present) , Gait disturbance (present) , Dystonic disorder (present) , Exaggerated startle response (present) , Drooling (present) , EEG abnormality (present) , Elevated circulating aspartate aminotransferase concentration (present) , Decreased CSF neopterin level (present) , Decreased CSF biopterin level (present) , Overfriendliness (present) (less)
Age: 10-19 years
Sex: female
Tissue: Blood
|
|
|
Uncertain significance
(May 05, 2017)
|
Flagged submission
flagged submission
Method: provider interpretation, clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Not Provided
Affected status: unknown
Allele origin:
de novo
|
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System
Accession: SCV000804327.2
First in ClinVar: Sep 08, 2018 Last updated: Dec 11, 2022 |
Comment:
This 3 year old female has a history of global developmental delay, absent speech, and seizures. The variant is absent from the gnomAD and ExAC … (more)
This 3 year old female has a history of global developmental delay, absent speech, and seizures. The variant is absent from the gnomAD and ExAC databases, and it was found to be de novo (with maternity and paternity confirmed). Computational prediction models predict the variant would be damaging to protein structure and/or function. This is a gene of uncertain significance; no known human disorders have been clearly associated with this gene. (less)
Observation 1:
Clinical Features:
Global developmental delay (present) , Absent speech (present) , Seizures (present)
Age: 0-9 years
Sex: female
Secondary finding: no
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-04-03
Testing laboratory interpretation: Uncertain significance
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Absent speech (present) , Seizures (present)
Age: 0-9 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-04-03
Testing laboratory interpretation: Uncertain significance
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PS3_SUP, PM2_SUP, PP2, PP3
Comment:
Criteria applied: PS3_MOD, PS4_MOD, PM2_SUP, PP2, PP3
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 741 of the ATP6V0A1 protein (p.Arg741Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ATP6V0A1-related conditions (PMID: 28135719, 33833240; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 560227). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").
Comment:
Criteria applied: PS3_MOD,PS4_MOD,PM2_SUP,PP2,PP3
Comment:
This 3 year old female has a history of global developmental delay, absent speech, and seizures. The variant is absent from the gnomAD and ExAC databases, and it was found to be de novo (with maternity and paternity confirmed). Computational prediction models predict the variant would be damaging to protein structure and/or function. This is a gene of uncertain significance; no known human disorders have been clearly associated with this gene.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The c.2222G>A (p.R741Q) alteration is located in exon 19 (coding exon 18) of the ATP6V0A1 gene. This alteration results from a G to A substitution at nucleotide position 2222, causing the arginine (R) at amino acid position 741 to be replaced by a glutamine (Q)._x000D_ _x000D_ for autosomal dominant ATP6V0A1-related developmental and epileptic encephalopathy; however, its clinical significance for autosomal recessive ATP6V0A1-related neurodevelopmental disorder is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, also known as c.2219G>A (p.R740Q), was reported de novo in ten patients with developmental and epileptic encephalopathy (Aoto, 2021; Bott, 2021). This amino acid position is highly conserved in available vertebrate species. The R741Q (aka R740Q) variant is located in a critical transmembrane domain that may inhibit glutamate deprotonation. In vitro functional studies of the R740Q variant demonstrated altered organelle acidification and failure of lysosomal hydrolysis impairing canonical proton-pumping V-ATPase function. In addition, homozygote nematodes carrying the corresponding R740Q mutation showed severe developmental arrest at early larval stage (Bott, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PS3_SUP, PM2_SUP, PP2, PP3
Comment:
Criteria applied: PS3_MOD, PS4_MOD, PM2_SUP, PP2, PP3
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 741 of the ATP6V0A1 protein (p.Arg741Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ATP6V0A1-related conditions (PMID: 28135719, 33833240; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 560227). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").
Comment:
Criteria applied: PS3_MOD,PS4_MOD,PM2_SUP,PP2,PP3
Comment:
This 3 year old female has a history of global developmental delay, absent speech, and seizures. The variant is absent from the gnomAD and ExAC databases, and it was found to be de novo (with maternity and paternity confirmed). Computational prediction models predict the variant would be damaging to protein structure and/or function. This is a gene of uncertain significance; no known human disorders have been clearly associated with this gene.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy. | Bott LC | Brain communications | 2021 | PMID: 34909687 |
| ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H(+)-ATPases is essential for brain development in humans and mice. | Aoto K | Nature communications | 2021 | PMID: 33833240 |
| Prevalence and architecture of de novo mutations in developmental disorders. | Deciphering Developmental Disorders Study | Nature | 2017 | PMID: 28135719 |
Text-mined citations for rs1567871600 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.