ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.4091C>T (p.Ala1364Val)
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_000492.4(CFTR):c.4091C>T (p.Ala1364Val)
Variation ID: 53885 Accession: VCV000053885.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117664815 (GRCh38) [ NCBI UCSC ] 7: 117304869 (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 Jan 25, 2018 May 1, 2024 Jun 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.4091C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ala1364Val missense NC_000007.14:g.117664815C>T NC_000007.13:g.117304869C>T NG_016465.4:g.204032C>T LRG_663:g.204032C>T LRG_663t1:c.4091C>T LRG_663p1:p.Ala1364Val P13569:p.Ala1364Val - Protein change
- A1364V
- Other names
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- Canonical SPDI
- NC_000007.14:117664814:C:T
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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.
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
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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CFTR | - | - |
GRCh38 GRCh37 |
3703 | 5024 |
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
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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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Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Dec 5, 2022 | RCV000576913.10 | |
Uncertain significance (1) |
criteria provided, multiple submitters, no conflicts
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Dec 30, 2017 | RCV000761478.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 18, 2023 | RCV000781271.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 15, 2023 | RCV003415805.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 13, 2023 | RCV003480046.2 |
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. |
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Uncertain significance
(Dec 04, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000796159.1
First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018 |
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Uncertain significance
(Oct 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001570626.3
First in ClinVar: Apr 13, 2021 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1364 of the CFTR protein (p.Ala1364Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1364 of the CFTR protein (p.Ala1364Val). This variant is present in population databases (rs397508670, gnomAD 0.02%). This missense change has been observed in individuals with congenital bilateral absence of vas deferens and/or pancreatitis (PMID: 10200050, 17003641, 21520337). ClinVar contains an entry for this variant (Variation ID: 53885). 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 expected to disrupt CFTR protein function. 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
(Jun 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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CFTR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004109850.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CFTR c.4091C>T variant is predicted to result in the amino acid substitution p.Ala1364Val. This variant is predicted to generate a cryptic splicing donor site … (more)
The CFTR c.4091C>T variant is predicted to result in the amino acid substitution p.Ala1364Val. This variant is predicted to generate a cryptic splicing donor site based on available splicing prediction programs (Alamut Visual Plus v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. This variant has been reported in the heterozygous state in multiple individuals with congenital absence of vas deferens, and in one individual was reported along with a p.Phe508del variant (de Meeus et al. 1997. PubMed ID: 10200050; Supporting Table S5, Steiner et al. 2011. PubMed ID: 21520337; Table 1, Luo et al. 2020. PubMed ID: 32777524). This variant has also been reported in the heterozygous state in an individual with pancreatitis (Table 2, Keiles et al. 2006. PubMed ID: 17003641). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117304869-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Apr 20, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224097.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM2
Number of individuals with the variant: 1
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Uncertain significance
(Jun 13, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048685.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024 |
Comment:
The CFTR c.4091C>T; p.Ala1364Val variant (rs397508670) is reported in the literature in two individuals affected with CBAVD co-occurring with another pathogenic CFTR variant (de Meeus … (more)
The CFTR c.4091C>T; p.Ala1364Val variant (rs397508670) is reported in the literature in two individuals affected with CBAVD co-occurring with another pathogenic CFTR variant (de Meeus 1998, Luo 2021). In addition, this variant had been reported as heterozygous in an individual with pancreatitis (Keiles 2006). This variant is also reported in ClinVar (Variation ID: 53885). This variant is found in the general population with an allele frequency of 0.004% (9/251250 alleles) in the Genome Aggregation Database. The alanine at codon 1364 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.754). However, given the lack of clinical and functional data, the significance of the p.Ala1364Val variant is uncertain at this time. References: de Meeus A et al. Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online. Hum Mutat. 1998;11(6):480. PMID: 10200050. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Luo S et al. Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. Gene. 2021 Jan 10;765:145045. PMID: 32777524. (less)
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Uncertain significance
(Dec 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002629311.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A1364V variant (also known as c.4091C>T), located in coding exon 25 of the CFTR gene, results from a C to T substitution at nucleotide … (more)
The p.A1364V variant (also known as c.4091C>T), located in coding exon 25 of the CFTR gene, results from a C to T substitution at nucleotide position 4091. The alanine at codon 1364 is replaced by valine, an amino acid with similar properties. This variant was reported in conjunction with p.F508del in an individual with congenital absence of the vas deferens (CBAVD) (de Meeus A et al. Hum. Mutat., 1998;11:480). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Dec 30, 2017)
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criteria provided, single submitter
Method: curation
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Hereditary pancreatitis
Affected status: yes
Allele origin:
unknown
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Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891591.1
First in ClinVar: Mar 24, 2019 Last updated: Mar 24, 2019 |
Geographic origin: Middle East
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Uncertain significance
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002027537.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Uncertain significance
(May 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919183.2
First in ClinVar: Jun 02, 2019 Last updated: Jun 24, 2023 |
Comment:
Variant summary: CFTR c.4091C>T (p.Ala1364Val) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. … (more)
Variant summary: CFTR c.4091C>T (p.Ala1364Val) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 255050 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (3.9e-05 vs 0.013), allowing no conclusion about variant significance. c.4091C>T has been reported in the literature as a compound heterozygous genotype with p.F508del in at-least one individual affected with CAVD (example, deMeeus_1997) or in the absense of a second variant (example, Luo_2021). It has also been reported in heterozygote inviduals affected with pancreatitis (example, Keiles_2006) or with a CF-like disorder associated with AGR2 mutations, in which the patient had a negative sweat chloride test (Bertolli-Avella_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17003641, 20059485, 21520337, 22483971, 11504857, 10200050, 25735457, 26277102, 25880441, 32777524, 34740355, 34952832, 35913788). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance (n=6). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454293.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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CFTR-related disorders
Affected status: yes
Allele origin:
germline
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000679397.1
First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018 |
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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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Heterogeneous spectrum of CFTR gene mutations in Chinese patients with CAVD and the dilemma of genetic blocking strategy. | Feng J | Reproduction (Cambridge, England) | 2022 | PMID: 35913788 |
A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene. | Bertoli-Avella A | Journal of medical genetics | 2022 | PMID: 34952832 |
Frequency of allele variations in the CFTR gene in a Mexican population. | Cantú-Reyna C | BMC medical genomics | 2021 | PMID: 34740355 |
Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. | Luo S | Gene | 2021 | PMID: 32777524 |
Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis. | Sanders M | Human genetics | 2021 | PMID: 32734384 |
Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk. | Lim RM | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 25880441 |
Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations. | Ramalho AS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2016 | PMID: 25735457 |
Novel mutations and polymorphisms in the CFTR gene associated with three subtypes of congenital absence of vas deferens. | Yang X | Fertility and sterility | 2015 | PMID: 26277102 |
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. | Li H | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2012 | PMID: 22483971 |
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? | Dorfman R | Clinical genetics | 2010 | PMID: 20059485 |
Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. | Keiles S | Pancreas | 2006 | PMID: 17003641 |
A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models. | Chen JM | Molecular biology and evolution | 2001 | PMID: 11504857 |
Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online. | de Meeus A | Human mutation | 1998 | PMID: 10200050 |
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Text-mined citations for rs397508670 ...
HelpRecord last updated May 01, 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.