ClinVar Genomic variation as it relates to human health
NM_000052.7(ATP7A):c.1933C>T (p.Arg645Ter)
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_000052.7(ATP7A):c.1933C>T (p.Arg645Ter)
Variation ID: 210404 Accession: VCV000210404.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq21.1 X: 78011239 (GRCh38) [ NCBI UCSC ] X: 77266736 (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 Oct 5, 2015 Feb 28, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000052.7:c.1933C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000043.4:p.Arg645Ter nonsense NM_001282224.2:c.1933C>T NP_001269153.1:p.Arg645Ter nonsense NC_000023.11:g.78011239C>T NC_000023.10:g.77266736C>T NG_013224.2:g.105543C>T - Protein change
- R645*
- Other names
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- Canonical SPDI
- NC_000023.11:78011238:C:T
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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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ATP7A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1929 | 2111 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Apr 3, 2020 | RCV000193235.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2017 | RCV000757017.8 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 11, 2024 | RCV001271473.7 |
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 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Menkes disease
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000246657.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Aug 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885042.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
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Pathogenic
(Apr 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Menkes kinky-hair syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338560.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
Comment:
Variant summary: ATP7A c.1933C>T (p.Arg645X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ATP7A c.1933C>T (p.Arg645X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 183238 control chromosomes (gnomAD). c.1933C>T has been reported in the literature in multiple individuals affected with Menkes kinky-hair syndrome (e.g. Das_1994, Hahn_2001, Mohamed_2015, Tumer_1997). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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X-linked distal spinal muscular atrophy type 3
Cutis laxa, X-linked Menkes kinky-hair syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002238921.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg645*) in the ATP7A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg645*) in the ATP7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7A are known to be pathogenic (PMID: 11241493, 20652413). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ATP7A-related conditions (PMID: 7977350, 32005694). ClinVar contains an entry for this variant (Variation ID: 210404). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 18, 2018)
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no assertion criteria provided
Method: clinical testing
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Menkes kinky-hair syndrome
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000844970.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
Comment:
The observed variant c.1933C>T has not been reported in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is damaging by … (more)
The observed variant c.1933C>T has not been reported in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is damaging by MutationTaster2 and LRT. (less)
Clinical Features:
Seizure (present) , Global developmental delay (present) , Severe failure to thrive (present) , Abnormality of hair texture (present) , Generalized hypotonia (present) , Fever … (more)
Seizure (present) , Global developmental delay (present) , Severe failure to thrive (present) , Abnormality of hair texture (present) , Generalized hypotonia (present) , Fever (present) , Decreased circulating ceruloplasmin concentration (present) , Pallor (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Indian Hindu
Geographic origin: India
Method: DNA was used to perform targeted gene sequencing using a custom capture kit. Libraries were sequenced to mean >80-100X coverage in Illumina sequencing platform. Sequence obtained were aligned to human reference genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Distal spinal muscular atrophy, X-linked 3
Cutis laxa, X-linked Menkes kinky-hair syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001452640.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Uncertain significance
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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Menkes kinky-hair syndrome
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004011996.1
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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Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort. | Dong X | Journal of medical genetics | 2020 | PMID: 32005694 |
Neurometabolic Disorders-Related Early Childhood Epilepsy: A Single-Center Experience in Saudi Arabia. | Mohamed S | Pediatrics and neonatology | 2015 | PMID: 26117549 |
A high-throughput resequencing microarray for autosomal dominant spastic paraplegia genes. | Dufke C | Neurogenetics | 2012 | PMID: 22552817 |
Molecular correlates of epilepsy in early diagnosed and treated Menkes disease. | Kaler SG | Journal of inherited metabolic disease | 2010 | PMID: 20652413 |
Identification of four novel mutations in classical Menkes disease and successful prenatal DNA diagnosis. | Hahn S | Molecular genetics and metabolism | 2001 | PMID: 11350187 |
ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome. | Gu YH | American journal of medical genetics | 2001 | PMID: 11241493 |
Identification of point mutations in 41 unrelated patients affected with Menkes disease. | Tümer Z | American journal of human genetics | 1997 | PMID: 8981948 |
Diverse mutations in patients with Menkes disease often lead to exon skipping. | Das S | American journal of human genetics | 1994 | PMID: 7977350 |
Text-mined citations for rs72554640 ...
HelpRecord last updated Mar 05, 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.