ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.4963A>G (p.Thr1655Ala)
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.
Uncertain significance(12); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.4963A>G (p.Thr1655Ala)
Variation ID: 236610 Accession: VCV000236610.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112840557 (GRCh38) [ NCBI UCSC ] 5: 112176254 (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 Jul 1, 2016 Apr 20, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.4963A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Thr1655Ala missense NM_001127510.3:c.4963A>G NP_001120982.1:p.Thr1655Ala missense NM_001127511.3:c.4909A>G NP_001120983.2:p.Thr1637Ala missense NM_001354895.2:c.4963A>G NP_001341824.1:p.Thr1655Ala missense NM_001354896.2:c.5017A>G NP_001341825.1:p.Thr1673Ala missense NM_001354897.2:c.4993A>G NP_001341826.1:p.Thr1665Ala missense NM_001354898.2:c.4888A>G NP_001341827.1:p.Thr1630Ala missense NM_001354899.2:c.4879A>G NP_001341828.1:p.Thr1627Ala missense NM_001354900.2:c.4840A>G NP_001341829.1:p.Thr1614Ala missense NM_001354901.2:c.4786A>G NP_001341830.1:p.Thr1596Ala missense NM_001354902.2:c.4690A>G NP_001341831.1:p.Thr1564Ala missense NM_001354903.2:c.4660A>G NP_001341832.1:p.Thr1554Ala missense NM_001354904.2:c.4585A>G NP_001341833.1:p.Thr1529Ala missense NM_001354905.2:c.4483A>G NP_001341834.1:p.Thr1495Ala missense NM_001354906.2:c.4114A>G NP_001341835.1:p.Thr1372Ala missense NC_000005.10:g.112840557A>G NC_000005.9:g.112176254A>G NG_008481.4:g.153037A>G LRG_130:g.153037A>G LRG_130t1:c.4963A>G - Protein change
- T1637A, T1655A, T1614A, T1673A, T1495A, T1564A, T1627A, T1665A, T1372A, T1529A, T1554A, T1596A, T1630A
- Other names
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- Canonical SPDI
- NC_000005.10:112840556:A:G
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 | ||
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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
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. |
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APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14091 | 14225 |
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. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2023 | RCV000233240.20 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 18, 2023 | RCV000567766.18 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2023 | RCV000590193.21 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 18, 2021 | RCV002487042.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 1, 2023 | RCV003650527.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003998672.1 |
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. |
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Uncertain significance
(Apr 13, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694065.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The APC c.4963A>G (p.Thr1655Ala) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low … (more)
Variant summary: The APC c.4963A>G (p.Thr1655Ala) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. This variant was found in 1/123124 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a Variant of Uncertain Significance (VUS), until additional information becomes available. (less)
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Uncertain significance
(Jul 31, 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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PreventionGenetics, part of Exact Sciences
Accession: SCV000805417.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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Uncertain significance
(Nov 15, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002534942.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Nov 19, 2020)
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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: SCV000667457.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: 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)
Number of individuals with the variant: 1
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Uncertain significance
(Jun 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488792.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
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Uncertain significance
(Aug 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer
Hepatocellular carcinoma Desmoid disease, hereditary Familial adenomatous polyposis 1 Familial adenomatous polyposis 1 Gastric cancer Gastric adenocarcinoma and proximal polyposis of the stomach
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002786017.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Mar 03, 2023)
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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: SCV000566474.8
First in ClinVar: Apr 29, 2017 Last updated: Jun 03, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer and/or polyps, breast cancer, and glioma … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer and/or polyps, breast cancer, and glioma (Tung et al., 2015; Zhang et al., 2015; Rosenthal et al., 2018); This variant is associated with the following publications: (PMID: 25186627, 18199528, 30267214, 26580448) (less)
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Uncertain significance
(Feb 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019022.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Oct 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004195782.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Sep 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000887528.3
First in ClinVar: Mar 13, 2019 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals affected with colorectal cancer (PMID: 30267214 (2018)), glioma (PMID: 26580448 (2015)), and breast cancer … (more)
In the published literature, this variant has been reported in individuals affected with colorectal cancer (PMID: 30267214 (2018)), glioma (PMID: 26580448 (2015)), and breast cancer (PMID: 25186627 (2015)). The frequency of this variant in the general population, 0.000044 (5/113144 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Apr 18, 2023)
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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: SCV000681698.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with alanine at codon 1655 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with alanine at codon 1655 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with glioma, breast and colorectal cancer in the literature (PMID: 25186627, 26580448,30267214), and has been reported in a healthy individual (PMID: 18199528). This variant has been identified in 6/250776 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000282768.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1655 of the APC protein (p.Thr1655Ala). … (more)
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1655 of the APC protein (p.Thr1655Ala). This variant is present in population databases (rs759441332, gnomAD 0.002%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 30267214). ClinVar contains an entry for this variant (Variation ID: 236610). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Classic or attenuated familial adenomatous polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004837988.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces threonine with alanine at codon 1655 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with alanine at codon 1655 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with glioma and breast and colorectal cancer in the literature (PMID: 25186627, 26580448,30267214), and has been reported in a healthy individual (PMID: 18199528). This variant has been identified in 6/250776 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 6
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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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TAPES: A tool for assessment and prioritisation in exome studies. | Xavier A | PLoS computational biology | 2019 | PMID: 31613886 |
Rare loss of function variants in candidate genes and risk of colorectal cancer. | Rosenthal EA | Human genetics | 2018 | PMID: 30267214 |
Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
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 |
Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. | Azzopardi D | Cancer research | 2008 | PMID: 18199528 |
Text-mined citations for rs759441332 ...
HelpRecord last updated Apr 20, 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.