ClinVar Genomic variation as it relates to human health
NM_152424.4(AMER1):c.1489C>T (p.Arg497Ter)
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_152424.4(AMER1):c.1489C>T (p.Arg497Ter)
Variation ID: 862773 Accession: VCV000862773.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq11.2 X: 64191798 (GRCh38) [ NCBI UCSC ] X: 63411678 (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 Apr 15, 2020 Feb 20, 2024 May 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_152424.4:c.1489C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689637.3:p.Arg497Ter nonsense NC_000023.11:g.64191798G>A NC_000023.10:g.63411678G>A NG_021345.1:g.18947C>T LRG_1259:g.18947C>T LRG_1259t1:c.1489C>T LRG_1259p1:p.Arg497Ter - Protein change
- R497*
- Other names
- NM_152424.4(AMER1):c.1489C>T
- p.Arg497Ter
- Canonical SPDI
- NC_000023.11:64191797: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
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The frequency of the allele represented by this VCV record.
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- Links
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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AMER1 | - | - |
GRCh38 GRCh37 |
430 | 561 |
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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 13, 2022 | RCV001069565.8 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 2, 2023 | RCV001775155.4 |
Submissions - Germline
Classification
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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
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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
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Osteopathia striata with cranial sclerosis
Affected status: yes
Allele origin:
maternal
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3billion
Accession: SCV002012055.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000862773.2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cortical dysplasia (present) , Global developmental delay (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Depressed nasal bridge (present) , … (more)
Cortical dysplasia (present) , Global developmental delay (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Depressed nasal bridge (present) , Frontal bossing (present) , Delayed gross motor development (present) , Hypertelorism (present) , Intellectual disability (present) , Macrocephaly (present) , Premature birth (present) , Delayed speech and language development (present) , Polymicrogyria (present) (less)
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Likely pathogenic
(Dec 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002765212.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Nonsense variant predicted to result in protein truncation, as the last 639 amino acids are lost, and other loss-of-function variants have been reported downstream in … (more)
Nonsense variant predicted to result in protein truncation, as the last 639 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously reported as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 22043478, 19079258, 26071483) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Osteopathia striata with cranial sclerosis
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003853261.1
First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023 |
Comment:
"A Nonsense variant c.1489C>T in Exon 2 of the AMER1 gene that results in premature truncation of the protein (p.Arg497*) was identified. The observed variant … (more)
"A Nonsense variant c.1489C>T in Exon 2 of the AMER1 gene that results in premature truncation of the protein (p.Arg497*) was identified. The observed variant has a minor allele frequency of 0.00% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant was found in ClinVar (Variant ID :862773) with a classification of Pathogenic/Likely Pathogenic and a review status of (2 star) criteria provided, multiple submitters, no conflicts. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines." (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Likely pathogenic
(May 02, 2023)
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criteria provided, single submitter
Method: curation
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Osteopathia striata with cranial sclerosis
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003922295.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
The hemizygous p.Arg497Ter variant in AMER1 was identified by our study in one individual with myopathy, seizures, and central hypoventilation. The p.Arg497Ter variant in AMER1 … (more)
The hemizygous p.Arg497Ter variant in AMER1 was identified by our study in one individual with myopathy, seizures, and central hypoventilation. The p.Arg497Ter variant in AMER1 has been previously reported in 2 unrelated individuals with X-linked osteopathia striata with cranial sclerosis (ClinVar SCV002012055.1, SCV003853261.1). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 862773) and has been interpreted as pathogenic by 3billion and LifeCell International Pvt. Ltd and as likely pathogenic by Invitae and GeneDx. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 497. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the AMER1 gene is an established disease mechanism in X-linked osteopathia striata with cranial sclerosis. In summary, additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for X-linked osteopathia striata with cranial sclerosis. ACMG/AMP Criteria applied: PVS1_Strong, PS4_Supporting, PM2_Supporting (Richards 2015). (less)
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Likely pathogenic
(Feb 05, 2022)
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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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Invitae
Accession: SCV001234741.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 862773). This variant has not been reported in the literature in individuals affected with AMER1-related conditions. … (more)
ClinVar contains an entry for this variant (Variation ID: 862773). This variant has not been reported in the literature in individuals affected with AMER1-related conditions. This variant is not present in population databases (gnomAD no frequency). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the C-terminus of the AMER1 protein. Other variant(s) that disrupt this region (p.Leu546Phefs*34, p.Arg531*, p.Asp503Metfs*38) have been observed in individuals with AMER1-related conditions (PMID: 19079258, 22043478). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change creates a premature translational stop signal (p.Arg497*) in the AMER1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 639 amino acid(s) of the AMER1 protein. (less)
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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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The male phenotype in osteopathia striata congenita with cranial sclerosis. | Holman SK | American journal of medical genetics. Part A | 2011 | PMID: 22043478 |
Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. | Jenkins ZA | Nature genetics | 2009 | PMID: 19079258 |
Text-mined citations for rs1930251154 ...
HelpRecord last updated Mar 30, 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.