ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.9019G>T (p.Glu3007Ter)
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_000051.4(ATM):c.9019G>T (p.Glu3007Ter)
Variation ID: 233403 Accession: VCV000233403.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108365356 (GRCh38) [ NCBI UCSC ] 11: 108236083 (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 9, 2016 Feb 20, 2024 Apr 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000051.4:c.9019G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Glu3007Ter nonsense NM_001330368.2:c.640+20564C>A intron variant NM_001351110.2:c.694+20564C>A intron variant NM_001351834.2:c.9019G>T NP_001338763.1:p.Glu3007Ter nonsense NC_000011.10:g.108365356G>T NC_000011.9:g.108236083G>T NG_009830.1:g.147525G>T NG_054724.1:g.109477C>A LRG_135:g.147525G>T LRG_135t1:c.9019G>T LRG_135p1:p.Glu3007Ter - Protein change
- E3007*
- Other names
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- Canonical SPDI
- NC_000011.10:108365355:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- termination codon change Variation Ontology [VariO:0309]
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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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ATM | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10001 | 16103 | |
C11orf65 | - | - | - |
GRCh38 GRCh37 |
3 | 6086 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2022 | RCV000222768.15 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2023 | RCV000233073.21 | |
Likely pathogenic (5) |
criteria provided, single submitter
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Aug 6, 2018 | RCV000255661.15 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 23, 2022 | RCV001854694.9 |
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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Likely pathogenic
(Aug 06, 2018)
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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: SCV000322216.6
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Comment:
This variant is denoted ATM c.9019G>T at the cDNA level and p.Glu3007Ter (E3007X) at the protein level. The substitution creates a nonsense variant, which changes … (more)
This variant is denoted ATM c.9019G>T at the cDNA level and p.Glu3007Ter (E3007X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through protein truncation. Due to the position of the variant, nonsense mediated decay is not expected to occur, but it is predicted to cause loss of normal protein function through protein truncation as the last 49 amino acids are no longer translated. The disrupted region at the end of the gene is located within the FATC domain (Stracker 2013). This variant has been reported in an individual with Ataxia-telangiectasia and in at least two individuals with breast cancer (Broeks 1998, Tung 2015, Hauke 2018). We consider ATM Glu3007Ter to be a likely pathogenic variant. (less)
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Pathogenic
(Apr 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001340249.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 08, 2022 |
Comment:
This variant changes 1 nucleotide in exon 63 of the ATM gene, creating a premature translation stop signal in the last coding exon. While this … (more)
This variant changes 1 nucleotide in exon 63 of the ATM gene, creating a premature translation stop signal in the last coding exon. While this mutant transcript is predicted to escape the nonsense-mediated decay and be expressed as a truncated protein, this C-terminally truncated protein is expected to disrupt the TP53 binding domain and FATC domain and to affect normal ATM protein function (PMID: 19779456). In addition, a truncating variant (p.Arg3047*) occurring downstream of this variant is known to be disease-causing (ClinVar variation ID: 3029), suggesting that the truncated region is important for protein structure and function. This variant has been reported in an individual affected with ataxia telangiectasia (PMID: 9792409). This variant has also been reported in individuals affected with breast cancer (PMID: 25186627, 29522266). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000277771.7
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.E3007* pathogenic mutation (also known as c.9019G>T), located in coding exon 62 of the ATM gene, results from a G to T substitution at … (more)
The p.E3007* pathogenic mutation (also known as c.9019G>T), located in coding exon 62 of the ATM gene, results from a G to T substitution at nucleotide position 9019. This changes the amino acid from a glutamic acid to a stop codon within coding exon 62. This alteration occurs at the 3' terminus of theATM gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 50 amino acids of the protein. However, premature stop codons are typically deleterious in nature, and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in a compound heterozygous state in a Dutch individual with ataxia telangiectasia (Broeks A et al. Hum. Mutat. 1998;12:330-7). This alteration has also been reported in a breast cancer patient undergoing multi-gene panel testing (Tung N et al. Cancer. 2015 Jan 1;121(1):25-33), in 1/535 pancreatic ductal adenocarcinoma patients (Zimmermann MT et al. Front Oncol, 2021 Mar;11:606820), and in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Apr 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024404.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Apr 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000283103.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ATM protein in which other variant(s) (p.Arg3047*) have … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ATM protein in which other variant(s) (p.Arg3047*) have been determined to be pathogenic (PMID: 8755918, 10980530, 18560558, 19431188, 19691550, 26628246). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 233403). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 9792409, 25186627). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu3007*) in the ATM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acid(s) of the ATM protein. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807334.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741557.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001906245.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001951856.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Mar 23, 2022)
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no assertion criteria provided
Method: clinical testing
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clear cell renal cell carcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Michigan Center for Translational Pathology, University of Michigan
Accession: SCV002107489.1
First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
Comment:
ATM c.9019G>T; p.E3007* noted in a 36 year old female with aggressive, metastatic RCC and a significant family history of cancer (including father diagnosed with … (more)
ATM c.9019G>T; p.E3007* noted in a 36 year old female with aggressive, metastatic RCC and a significant family history of cancer (including father diagnosed with RCC at age 59, who died of rapidly progressive disease) with the tumor showing somatic loss of heterozygosity (LOH) by uniparental disomy. The substitution in ATM induces a nonsense variant, which truncates the final 49 amino acid residues from the C-terminal, expected to disrupt the TP53 binding domain and FATC domain and to affect normal ATM protein function (PMID: 19779456). Ataxia telangiectasia mutated gene (ATM) plays a critical role in DNA repair and response to double strand breaks. ATM is associated with increased risk of breast cancer, pancreatic cancer and prostate cancer. (less)
Age: 30-39 years
Sex: female
Ethnicity/Population group: Caucasian
Comment on evidence:
Loss of heterozygosity by uniparental disomy
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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termination codon change
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Michigan Center for Translational Pathology, University of Michigan
Accession: SCV002107489.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Interpreting Sequence Variation in PDAC-Predisposing Genes Using a Multi-Tier Annotation Approach Performed at the Gene, Patient, and Cohort Level. | Zimmermann MT | Frontiers in oncology | 2021 | PMID: 33747920 |
Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. | Hauke J | Cancer medicine | 2018 | PMID: 29522266 |
Novel ATM mutations with ataxia-telangiectasia. | Liu XL | Neuroscience letters | 2016 | PMID: 26628246 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Emerging common themes in regulation of PIKKs and PI3Ks. | Lempiäinen H | The EMBO journal | 2009 | PMID: 19779456 |
Founder effects for ATM gene mutations in Italian Ataxia Telangiectasia families. | Chessa L | Annals of human genetics | 2009 | PMID: 19691550 |
Modeling ATM mutant proteins from missense changes confirms retained kinase activity. | Barone G | Human mutation | 2009 | PMID: 19431188 |
Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. | Perfettini JL | PloS one | 2008 | PMID: 18560558 |
Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. | Laake K | Human mutation | 2000 | PMID: 10980530 |
ATM germline mutations in classical ataxia-telangiectasia patients in the Dutch population. | Broeks A | Human mutation | 1998 | PMID: 9792409 |
Mutations associated with variant phenotypes in ataxia-telangiectasia. | McConville CM | American journal of human genetics | 1996 | PMID: 8755918 |
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Text-mined citations for rs876660382 ...
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.