ClinVar Genomic variation as it relates to human health
NM_000701.8(ATP1A1):c.1798C>G (p.Pro600Ala)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000701.8(ATP1A1):c.1798C>G (p.Pro600Ala)
Variation ID: 545678 Accession: VCV000545678.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p13.1 1: 116395247 (GRCh38) [ NCBI UCSC ] 1: 116937869 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jul 1, 2018 Apr 15, 2024 Apr 22, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000701.8:c.1798C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000692.2:p.Pro600Ala missense NM_001160233.1:c.1798C>G NM_001160233.2:c.1798C>G NP_001153705.1:p.Pro600Ala missense NM_001160234.2:c.1705C>G NP_001153706.1:p.Pro569Ala missense NC_000001.11:g.116395247C>G NC_000001.10:g.116937869C>G NG_047036.1:g.28063C>G - Protein change
- P600A, P569A
- Other names
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- Canonical SPDI
- NC_000001.11:116395246:C:G
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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ATP1A1 | - | - |
GRCh38 GRCh37 |
295 | 711 | |
ATP1A1-AS1 | - | - | GRCh38 | - | 401 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 22, 2022 | RCV000656713.5 | |
Uncertain significance (1) |
no assertion criteria provided
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Oct 7, 2017 | RCV003311871.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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. |
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charcot-marie-tooth disease, axonal, type 2DD
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557876.1
First in ClinVar: Aug 04, 2022 Last updated: Aug 04, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, axonal, type 2DD (MIM#618036) and hypomagnesemia, seizures, and mental retardation 2 (MIM#618314). Loss of function has been clearly established for missense variants however, there is currently no information in the literature on the mechanism of disease associated with ATP1A1 protein truncating variants (PMIDs: 29499166, 30388404; OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to alanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated helical linker region (PMID: 29499166). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Pro600Thr) variant has been reported in one American family with Charcot-Marie-Tooth type 2 disease where the variant was found to segregate in four affected individuals (PMID: 29499166). (SP) 0803 - This variant has limited previous evidence of pathogenicity. This variant has been reported in one Italian family with Charcot-Marie-Tooth type 2 disease (PMID: 29499166). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate in at least five affected individuals within the same family (PMID: 29499166). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Pluripotent stem cells (iPSCs) generated from patient fibroblasts demonstrated defective differentiation of neuronal precursors into mature motor neurons in vitro compared to control iPSCs (PMID: 31707753). Additionally, mutant ATP1A1 expressed in Xenopus oocytes demonstrated significantly reduced Na+-dependent currents and using ouabain survival assays in U2OS cells, Lassuthova et al. (2018) also showed that mutant constructs had significantly reduced cell viability significantly reduced cell viability (PMID: 29499166) . (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Apr 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charcot-marie-tooth disease, axonal, type 2DD
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503852.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace proline with alanine at codon 600 of the ATP1A1 protein, p.(Pro600Ala). The proline residue is evolutionarily conserved (100 … (more)
This sequence change is predicted to replace proline with alanine at codon 600 of the ATP1A1 protein, p.(Pro600Ala). The proline residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in a mutational hot spot in the helical linker region that couples ATP hydrolysis and phosphorylation domains (PMID: 29499166). There is a small physicochemical difference between proline and alanine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). It has been identified in at least two probands with sensorimotor axonal neuropathy and segregates with disease over three generations in a large family (PMID: 29499166, Royal Melbourne Hospital). Induced pluripotent stem cell-derived motor neurons from an affected individual demonstrated defective differentiation and absence of ATP1A1 expression (PMID: 31707753). Additionally, in vitro functional assays demonstrated significantly fewer Na+-dependent currents for the variant (PMID: 29499166). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Furthermore, a different missense change at this position (p.Pro600Thr) has been identified in a family with Charcot-Marie-Tooth disease (PMID: 29499166). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PM1, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP4. (less)
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Pathogenic
(Jun 28, 2018)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2DD
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000778853.1
First in ClinVar: Jul 01, 2018 Last updated: Jul 01, 2018 |
Comment on evidence:
In 5 affected members of a multigenerational Southern Italian family (family 2) with autosomal dominant axonal Charcot-Marie-Tooth disease type 2DD (CMT2DD; 618036), Lassuthova et al. … (more)
In 5 affected members of a multigenerational Southern Italian family (family 2) with autosomal dominant axonal Charcot-Marie-Tooth disease type 2DD (CMT2DD; 618036), Lassuthova et al. (2018) identified a heterozygous c.1798C-G transversion (c.1798C-G, NM_000701) in exon 13 of the ATP1A1 gene, resulting in a pro600-to-ala (P600A) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. The substitution occurred in the intracellular loop between transmembrane domains M4 and M5 where ATP binding and hydrolysis occur. In vitro electrophysiologic functional expression studies in Xenopus oocytes showed that the mutation resulted in significantly fewer Na(+)-dependent currents compared to wildtype, consistent with a loss of function and haploinsufficiency. (less)
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Uncertain significance
(Oct 07, 2017)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease type 2A2
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004011908.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Hereditary spastic paraplegia is a novel phenotype for germline de novo ATP1A1 mutation. | Stregapede F | Clinical genetics | 2020 | PMID: 31705535 |
Insights into the pathogenesis of ATP1A1-related CMT disease using patient-specific iPSCs. | Manganelli F | Journal of the peripheral nervous system : JPNS | 2019 | PMID: 31707753 |
Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability. | Schlingmann KP | American journal of human genetics | 2018 | PMID: 30388404 |
Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. | Lassuthova P | American journal of human genetics | 2018 | PMID: 29499166 |
Identification of point mutations in 41 unrelated patients affected with Menkes disease. | Tümer Z | American journal of human genetics | 1997 | PMID: 8981948 |
Text-mined citations for rs1553192091 ...
HelpRecord last updated Apr 15, 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.