Experimental studies have shown that this missense change affects ALK function (PMID: 18923523, 18923525). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 18083). This missense change has been observed in individual(s) with neuroblastoma (PMID: 18724359, 18923523, 18923525, 29489754, 30350464; 18724359.). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1275 of the ALK protein (p.Arg1275Gln).
ClinVar Genomic variation as it relates to human health
NM_004304.5(ALK):c.3824G>A (p.Arg1275Gln)
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.
(11)
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004304.5(ALK):c.3824G>A (p.Arg1275Gln)
Variation ID: 18083 Accession: VCV000018083.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.2 2: 29209798 (GRCh38) [ NCBI UCSC ] 2: 29432664 (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 Apr 4, 2013 Nov 24, 2024 Jun 6, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004304.5:c.3824G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004295.2:p.Arg1275Gln missense NM_001353765.2:c.620G>A NP_001340694.1:p.Arg207Gln missense NC_000002.12:g.29209798C>T NC_000002.11:g.29432664C>T NG_009445.1:g.716769G>A LRG_488:g.716769G>A LRG_488t1:c.3824G>A Q9UM73:p.Arg1275Gln - Protein change
- R1275Q, R207Q
- Other names
- -
- Canonical SPDI
- NC_000002.12:29209797:C:T
-
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. |
|||
| ALK | No evidence available | No evidence available |
GRCh38 GRCh37 |
5133 | 5173 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Jun 6, 2024 | RCV000019709.18 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000423720.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000432041.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Dec 26, 2014 | RCV000440978.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 23, 2020 | RCV001268655.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 29, 2022 | RCV002354167.2 |
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
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447738.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Neuroblastoma (present)
Sex: male
|
|
|
Pathogenic
(Dec 15, 2020)
|
criteria provided, single submitter
Method: research
|
Neuroblastoma, susceptibility to, 3
Affected status: yes
Allele origin:
germline
|
Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478107.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
|
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Pathogenic
(Apr 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neuroblastoma, susceptibility to, 3
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002224310.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
Experimental studies have shown that this missense change affects ALK function (PMID: 18923523, 18923525). For these reasons, this variant has been classified as Pathogenic. An … (more)
Experimental studies have shown that this missense change affects ALK function (PMID: 18923523, 18923525). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 18083). This missense change has been observed in individual(s) with neuroblastoma (PMID: 18724359, 18923523, 18923525, 29489754, 30350464; 18724359.). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1275 of the ALK protein (p.Arg1275Gln). (less)
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|
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Pathogenic
(Apr 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002619803.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R1275Q pathogenic mutation (also known as c.3824G>A), located in coding exon 25 of the ALK gene, results from a G to A substitution at … (more)
The p.R1275Q pathogenic mutation (also known as c.3824G>A), located in coding exon 25 of the ALK gene, results from a G to A substitution at nucleotide position 3824. The arginine at codon 1275 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in the germline of several unrelated families with neuroblastoma and confirmed de novo in at least one affected individual (Mossé YP et al. Nature, 2008 Oct;455:930-5, Janoueix-Lerosey I et al. Nature, 2008 Oct;455:967-70, Kudo K et al. Genes Chromosomes Cancer, 2018 12;57:665-669, Ambry internal data). In addition, this alteration has been shown to constitutively activate the ALK tyrosine kinase domain using a peptide phosphorylation assay (Bresler SC et al. Sci Transl Med, 2011 Nov;3:108ra114). Furthermore, this alteration was able to drive the transformation of NIH/3T3 cells in a transformation assay (Bresler SC et al. Cancer Cell, 2014 Nov;26:682-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
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Pathogenic
(Jun 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neuroblastoma, susceptibility to, 3
Affected status: yes
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV005402306.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
The ALK c.3824G>A (p.Arg1275Gln) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function and … (more)
The ALK c.3824G>A (p.Arg1275Gln) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function and this is supported by functional studies (PMID: 18923525). This variant has been reported in multiple individuals with neuroblastoma (PMID: 18724359, 18923523, 22071890, 23334666, 30350464, internal data). In summary, this variant meets criteria to be classified as pathogenic. (less)
|
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|
risk factor
(Mar 01, 2012)
|
no assertion criteria provided
Method: literature only
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NEUROBLASTOMA, SUSCEPTIBILITY TO, 3
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000040007.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 17, 2022 |
Comment on evidence:
In 5 independent families segregating neuroblastoma (NBLST3; 613014), Mosse et al. (2008) identified a 3824G-A transition in the ALK gene, resulting in an arg1275-to-gln (R1275Q) … (more)
In 5 independent families segregating neuroblastoma (NBLST3; 613014), Mosse et al. (2008) identified a 3824G-A transition in the ALK gene, resulting in an arg1275-to-gln (R1275Q) substitution. The mutation manifested incomplete penetrance but was not identified in 218 normal control chromosomes. The mutation occurs in the kinase activation loop of the protein and has a 91% probability of being an activating mutation. In 1 family an unaffected mutation-carrying mother transmitted the mutation to 3 offspring by 3 different fathers; each of these 3 offspring developed neuroblastoma. Janoueix-Lerosey et al. (2008) identified 1 family in which an unaffected mutation-carrying mother transmitted the mutation to 2 affected offspring, each by a different father. George et al. (2008) identified this mutation in a patient with neuroblastoma. Chen et al. (2008) identified the R1275Q substitution as a somatic mutation in several neuroblastoma tumor samples. Bourdeaut et al. (2012) identified a de novo heterozygous germline R1275Q mutation in a patient with perinatal onset of multifocal neuroblastoma. The mutation was also found in several tumors. (less)
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Pathogenic
(Oct 07, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Neuroblastoma, susceptibility to, 3
Affected status: yes
Allele origin:
somatic
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000256824.1
First in ClinVar: Nov 14, 2015 Last updated: Nov 14, 2015
Comment:
Clinical Testing
|
Number of individuals with the variant: 19
|
|
|
Likely pathogenic
(Dec 26, 2014)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of brain
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503770.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neuroblastoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503769.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Breast neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503771.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
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not provided
(-)
|
no classification provided
Method: literature only
|
Neuroblastoma, susceptibility to, 3
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000041068.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The p.R1275Q pathogenic mutation (also known as c.3824G>A), located in coding exon 25 of the ALK gene, results from a G to A substitution at nucleotide position 3824. The arginine at codon 1275 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in the germline of several unrelated families with neuroblastoma and confirmed de novo in at least one affected individual (Mossé YP et al. Nature, 2008 Oct;455:930-5, Janoueix-Lerosey I et al. Nature, 2008 Oct;455:967-70, Kudo K et al. Genes Chromosomes Cancer, 2018 12;57:665-669, Ambry internal data). In addition, this alteration has been shown to constitutively activate the ALK tyrosine kinase domain using a peptide phosphorylation assay (Bresler SC et al. Sci Transl Med, 2011 Nov;3:108ra114). Furthermore, this alteration was able to drive the transformation of NIH/3T3 cells in a transformation assay (Bresler SC et al. Cancer Cell, 2014 Nov;26:682-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The ALK c.3824G>A (p.Arg1275Gln) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function and this is supported by functional studies (PMID: 18923525). This variant has been reported in multiple individuals with neuroblastoma (PMID: 18724359, 18923523, 22071890, 23334666, 30350464, internal data). In summary, this variant meets criteria to be classified as pathogenic.
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:
Experimental studies have shown that this missense change affects ALK function (PMID: 18923523, 18923525). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 18083). This missense change has been observed in individual(s) with neuroblastoma (PMID: 18724359, 18923523, 18923525, 29489754, 30350464; 18724359.). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1275 of the ALK protein (p.Arg1275Gln).
Comment:
The p.R1275Q pathogenic mutation (also known as c.3824G>A), located in coding exon 25 of the ALK gene, results from a G to A substitution at nucleotide position 3824. The arginine at codon 1275 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in the germline of several unrelated families with neuroblastoma and confirmed de novo in at least one affected individual (Mossé YP et al. Nature, 2008 Oct;455:930-5, Janoueix-Lerosey I et al. Nature, 2008 Oct;455:967-70, Kudo K et al. Genes Chromosomes Cancer, 2018 12;57:665-669, Ambry internal data). In addition, this alteration has been shown to constitutively activate the ALK tyrosine kinase domain using a peptide phosphorylation assay (Bresler SC et al. Sci Transl Med, 2011 Nov;3:108ra114). Furthermore, this alteration was able to drive the transformation of NIH/3T3 cells in a transformation assay (Bresler SC et al. Cancer Cell, 2014 Nov;26:682-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The ALK c.3824G>A (p.Arg1275Gln) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function and this is supported by functional studies (PMID: 18923525). This variant has been reported in multiple individuals with neuroblastoma (PMID: 18724359, 18923523, 22071890, 23334666, 30350464, internal data). In summary, this variant meets criteria to be classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ALK-Related Neuroblastic Tumor Susceptibility. | Adam MP | - | 2024 | PMID: 20301782 |
| Generation of induced pluripotent stem cell lines from two Neuroblastoma patients carrying a germline ALK R1275Q mutation. | Marin Navarro A | Stem cell research | 2019 | PMID: 30605844 |
| Two siblings with familial neuroblastoma with distinct clinical phenotypes harboring an ALK germline mutation. | Kudo K | Genes, chromosomes & cancer | 2018 | PMID: 30350464 |
| Molecular Modeling for Structural Insights Concerning the Activation Mechanisms of F1174L and R1275Q Mutations on Anaplastic Lymphoma Kinase. | Jiang CH | Molecules (Basel, Switzerland) | 2018 | PMID: 30004444 |
| The landscape of genomic alterations across childhood cancers. | Gröbner SN | Nature | 2018 | PMID: 29489754 |
| Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
| ALK(R1275Q) perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN. | Ueda T | Oncogene | 2016 | PMID: 26829053 |
| Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
| ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. | Bresler SC | Cancer cell | 2014 | PMID: 25517749 |
| The genetic landscape of high-risk neuroblastoma. | Pugh TJ | Nature genetics | 2013 | PMID: 23334666 |
| The R1275Q neuroblastoma mutant and certain ATP-competitive inhibitors stabilize alternative activation loop conformations of anaplastic lymphoma kinase. | Epstein LF | The Journal of biological chemistry | 2012 | PMID: 22932897 |
| ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome. | Bourdeaut F | European journal of human genetics : EJHG | 2012 | PMID: 22071890 |
| Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. | Bresler SC | Science translational medicine | 2011 | PMID: 22072639 |
| Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684. | Schönherr C | The Biochemical journal | 2011 | PMID: 21838707 |
| The constitutive activity of the ALK mutated at positions F1174 or R1275 impairs receptor trafficking. | Mazot P | Oncogene | 2011 | PMID: 21242967 |
| Activating mutations in ALK provide a therapeutic target in neuroblastoma. | George RE | Nature | 2008 | PMID: 18923525 |
| Oncogenic mutations of ALK kinase in neuroblastoma. | Chen Y | Nature | 2008 | PMID: 18923524 |
| Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. | Janoueix-Lerosey I | Nature | 2008 | PMID: 18923523 |
| Identification of ALK as a major familial neuroblastoma predisposition gene. | Mossé YP | Nature | 2008 | PMID: 18724359 |
| http://docm.genome.wustl.edu/variants/ENST00000389048:c.3824G>A | - | - | - | - |
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Text-mined citations for rs113994087 ...
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.