VCV000133476.38 - ClinVar

NM_004304.5(ALK):c.4587C>G (p.Asp1529Glu)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Benign

12 out of 17 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004304.5(ALK):c.4587C>G (p.Asp1529Glu)

Variation ID: 133476 Accession: VCV000133476.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.2 2: 29193500 (GRCh38) [ NCBI UCSC ] 2: 29416366 (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	Jun 9, 2014	Apr 13, 2025	Feb 4, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_004304.5:c.4587C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004295.2:p.Asp1529Glu	missense
NM_001353765.2:c.1383C>G	NP_001340694.1:p.Asp461Glu	missense
NC_000002.12:g.29193500G>C
NC_000002.11:g.29416366G>C
NG_009445.1:g.733067C>G
LRG_488:g.733067C>G
LRG_488t1:c.4587C>G
	Q9UM73:p.Asp1529Glu

... more HGVS ... less HGVS

Protein change

D1529E, D461E

Other names

Canonical SPDI

NC_000002.12:29193499:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.42712 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.43349

Exome Aggregation Consortium (ExAC) 0.46002

The Genome Aggregation Database (gnomAD), exomes 0.46849

The Genome Aggregation Database (gnomAD) 0.47503

Trans-Omics for Precision Medicine (TOPMed) 0.48953

1000 Genomes Project 0.57288

1000 Genomes Project 30x 0.57558

Links

UniProtKB: Q9UM73#VAR_031044 dbSNP: rs1881421 ClinGen: CA156644 VarSome

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
Gene	OMIM	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	5599	5640

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.
not specified	Benign (6)	criteria provided, multiple submitters, no conflicts	Apr 5, 2016	RCV000119980.15
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Apr 27, 2016	RCV000588550.3
Neuroblastoma, susceptibility to, 3	Benign (7)	criteria provided, multiple submitters, no conflicts	Feb 4, 2025	RCV000616049.27
Hereditary cancer-predisposing syndrome	Benign (1)	criteria provided, single submitter	Dec 12, 2016	RCV000562954.3
Squamous cell lung carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 5, 2020	RCV001250937.3

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.
Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000310079.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Neuroblastoma, susceptibility to, 3 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000429914.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Apr 05, 2016) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000518937.4 First in ClinVar: Mar 08, 2017 Last updated: Apr 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Mar 29, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000538270.1 First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency (less) Method: Genome/Exome Filtration
Benign (Dec 12, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000664946.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Apr 27, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698298.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Comment: Variant summary: The c.4587C>G variant affects a non-conserved nucleotide, resulting in amino acid change from Asp to Glu. 4/4 in-silico tools predict benign outcome for … (more) Variant summary: The c.4587C>G variant affects a non-conserved nucleotide, resulting in amino acid change from Asp to Glu. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 55828/121360 control chromosomes (14197 homozygotes) at a frequency of 0.4600198, which is about 1104047 times of the maximal expected frequency of a pathogenic allele (0.0000004), suggesting this variant is benign. Taken together, this variant was classified as Benign. (less)
Benign (Sep 21, 2015) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Neuroblastoma, susceptibility to, 3 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744249.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Jan 15, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Neuroblastoma, susceptibility to, 3 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV000745622.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Nov 23, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Neuroblastoma, susceptibility to, 3 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000883388.10 First in ClinVar: Mar 17, 2018 Last updated: Mar 11, 2025
Benign (Feb 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neuroblastoma, susceptibility to, 3 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001733355.5 First in ClinVar: Jun 15, 2021 Last updated: Feb 25, 2025
Benign (Jul 07, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuroblastoma, susceptibility to, 3 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004015858.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005238680.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Neuroblastoma, susceptibility to, 3 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734184.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Likely pathogenic (May 05, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing, in vivo	Squamous Cell Lung Carcinoma Affected status: yes Allele origin: somatic	Faculté Pluridciplinaire Nador, Université Mohamed Premier Accession: SCV001250920.2 First in ClinVar: Aug 08, 2020 Last updated: Apr 13, 2025	Publications: DOI: 10.3389/fonc.2020.01215 DOI: 10.3389/fonc.2020.01215 Observation 1: Number of individuals with the variant: 1 Observation 2: Sex: male Tissue: Liver metastasis Tumor Result: Percentage of variant in tissue sample = 99.89%
Benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927364.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954961.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (Sep 19, 2013) N Not contributing to aggregate classification	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000084110.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Variant summary: The c.4587C>G variant affects a non-conserved nucleotide, resulting in amino acid change from Asp to Glu. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 55828/121360 control chromosomes (14197 homozygotes) at a frequency of 0.4600198, which is about 1104047 times of the maximal expected frequency of a pathogenic allele (0.0000004), suggesting this variant is benign. Taken together, this variant was classified as Benign.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Next-Generation Sequencing at High Sequencing Depth as a Tool to Study the Evolution of Metastasis Driven by Genetic Change Events of Lung Squamous Cell Carcinoma.	Mansour H	Frontiers in oncology	2020	DOI: 10.3389/fonc.2020.01215

Text-mined citations for rs1881421 ...

These 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 Apr 13, 2025

ClinVar Genomic variation as it relates to human health

NM_004304.5(ALK):c.4587C>G (p.Asp1529Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1881421 ...