DNA sequence analysis of the ATP1A3 gene demonstrated a sequence change, c.2324C>T, in exon 17 that results in an amino acid change, p.Pro775Leu. This sequence change is absent in the gnomAD population database. The p.Pro775Leu change has been previously described as a de novo variant in individuals with ATP1A3-related disorders (PMID: 32684337, https://n.neurology.org/content/94/15_Supplement/1946). The p.Pro775Leu change affects a moderately conserved amino acid residue located in a domain of the ATP1A3 protein that is known to be functional. The p.Pro775Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL, CADD). The vast majority of pathogenic variants in the ATP1A3 gene are missense with many located around the p.Pro775 region. In addition, the ATP1A3 gene appears to be relatively intolerant to missense changes. Collectively this evidence suggests p.Pro775Leu is likely pathogenic, however functional studies have not been performed to prove this conclusively.
ClinVar Genomic variation as it relates to human health
NM_152296.5(ATP1A3):c.2324C>T (p.Pro775Leu)
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_152296.5(ATP1A3):c.2324C>T (p.Pro775Leu)
Variation ID: 280121 Accession: VCV000280121.51
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 41970482 (GRCh38) [ NCBI UCSC ] 19: 42474634 (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 Dec 6, 2016 Oct 20, 2024 Sep 23, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_152296.5:c.2324C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689509.1:p.Pro775Leu missense NM_001256213.2:c.2357C>T NP_001243142.1:p.Pro786Leu missense NM_001256214.2:c.2363C>T NP_001243143.1:p.Pro788Leu missense NC_000019.10:g.41970482G>A NC_000019.9:g.42474634G>A NG_008015.1:g.28749C>T LRG_1186:g.28749C>T LRG_1186t1:c.2324C>T LRG_1186p1:p.Pro775Leu - Protein change
- P775L, P788L, P786L
- Other names
- -
- Canonical SPDI
- NC_000019.10:41970481:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
- -
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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. |
|||
| ATP1A3 | - | - |
GRCh38 GRCh37 |
1163 | 1184 | |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 23, 2024 | RCV000272828.34 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 3, 2018 | RCV001266079.4 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 16, 2023 | RCV001197881.13 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 17, 2023 | RCV003236579.3 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Sep 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002064420.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the ATP1A3 gene demonstrated a sequence change, c.2324C>T, in exon 17 that results in an amino acid change, p.Pro775Leu. This sequence … (more)
DNA sequence analysis of the ATP1A3 gene demonstrated a sequence change, c.2324C>T, in exon 17 that results in an amino acid change, p.Pro775Leu. This sequence change is absent in the gnomAD population database. The p.Pro775Leu change has been previously described as a de novo variant in individuals with ATP1A3-related disorders (PMID: 32684337, https://n.neurology.org/content/94/15_Supplement/1946). The p.Pro775Leu change affects a moderately conserved amino acid residue located in a domain of the ATP1A3 protein that is known to be functional. The p.Pro775Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL, CADD). The vast majority of pathogenic variants in the ATP1A3 gene are missense with many located around the p.Pro775 region. In addition, the ATP1A3 gene appears to be relatively intolerant to missense changes. Collectively this evidence suggests p.Pro775Leu is likely pathogenic, however functional studies have not been performed to prove this conclusively. (less)
|
|
|
Pathogenic
(Feb 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy 99
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004014002.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PS2, PM1, PM2, PM5, PP3, PP5
|
|
|
Pathogenic
(Nov 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Dystonia 12
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001555250.4
First in ClinVar: Apr 13, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 775 of the ATP1A3 protein (p.Pro775Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 775 of the ATP1A3 protein (p.Pro775Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ATP1A3-related conditions (PMID: 32684337; Invitae). This variant is also known as c.2363C>T p.Pro788Leu. ClinVar contains an entry for this variant (Variation ID: 280121). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A3 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro775 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33880529). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Sep 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329981.7
First in ClinVar: Dec 06, 2016 Last updated: Oct 08, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.2363C>T (p.Pro788Leu); This variant is associated with the following publications: (PMID: 33057194, 37541188, 35012964, 35982159, 37043503, 32684337) (less)
|
|
|
Likely pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Dystonia 12
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368664.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP2,PP3,PP5.
|
|
|
Likely pathogenic
(Dec 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001444251.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Cerebral palsy (present) , Esotropia (present) , Asthma (present) , Joint hypermobility (present) , Constipation (present) , Nystagmus (present) , Global developmental delay (present) , … (more)
Cerebral palsy (present) , Esotropia (present) , Asthma (present) , Joint hypermobility (present) , Constipation (present) , Nystagmus (present) , Global developmental delay (present) , Slender finger (present) , Hypoplasia of dental enamel (present) , Pes planus (present) , Muscular hypotonia (present) , Gait disturbance (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
|
|
|
Likely pathogenic
(Oct 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy 99
Affected status: yes
Allele origin:
germline
|
Eurofins-Biomnis
Accession: SCV003935047.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
|
|
|
Likely pathogenic
(Jun 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001151935.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 4
|
|
|
Uncertain significance
(May 01, 2017)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000609780.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
PS2, PM1, PM2, PM5, PP3, PP5
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 775 of the ATP1A3 protein (p.Pro775Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ATP1A3-related conditions (PMID: 32684337; Invitae). This variant is also known as c.2363C>T p.Pro788Leu. ClinVar contains an entry for this variant (Variation ID: 280121). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A3 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro775 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33880529). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.2363C>T (p.Pro788Leu); This variant is associated with the following publications: (PMID: 33057194, 37541188, 35012964, 35982159, 37043503, 32684337)
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP2,PP3,PP5.
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:
DNA sequence analysis of the ATP1A3 gene demonstrated a sequence change, c.2324C>T, in exon 17 that results in an amino acid change, p.Pro775Leu. This sequence change is absent in the gnomAD population database. The p.Pro775Leu change has been previously described as a de novo variant in individuals with ATP1A3-related disorders (PMID: 32684337, https://n.neurology.org/content/94/15_Supplement/1946). The p.Pro775Leu change affects a moderately conserved amino acid residue located in a domain of the ATP1A3 protein that is known to be functional. The p.Pro775Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL, CADD). The vast majority of pathogenic variants in the ATP1A3 gene are missense with many located around the p.Pro775 region. In addition, the ATP1A3 gene appears to be relatively intolerant to missense changes. Collectively this evidence suggests p.Pro775Leu is likely pathogenic, however functional studies have not been performed to prove this conclusively.
Comment:
PS2, PM1, PM2, PM5, PP3, PP5
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 775 of the ATP1A3 protein (p.Pro775Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ATP1A3-related conditions (PMID: 32684337; Invitae). This variant is also known as c.2363C>T p.Pro788Leu. ClinVar contains an entry for this variant (Variation ID: 280121). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A3 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro775 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33880529). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.2363C>T (p.Pro788Leu); This variant is associated with the following publications: (PMID: 33057194, 37541188, 35012964, 35982159, 37043503, 32684337)
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP2,PP3,PP5.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria. | Vetro A | Brain : a journal of neurology | 2021 | PMID: 33880529 |
| Movement disorders rounds: Atypical cases in two Chinese families with novel variants in ATP1A3. | Li XY | Parkinsonism & related disorders | 2020 | PMID: 32684337 |
| Structures and characterization of digoxin- and bufalin-bound Na+,K+-ATPase compared with the ouabain-bound complex. | Laursen M | Proceedings of the National Academy of Sciences of the United States of America | 2015 | PMID: 25624492 |
Text-mined citations for rs886041396 ...
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 Oct 20, 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.