ClinVar Genomic variation as it relates to human health
NM_000132.4(F8):c.222G>A (p.Thr74=)
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.
Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000132.4(F8):c.222G>A (p.Thr74=)
Variation ID: 618103 Accession: VCV000618103.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154999522 (GRCh38) [ NCBI UCSC ] X: 154227797 (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 Feb 18, 2019 Oct 8, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000132.4:c.222G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000123.1:p.Thr74= synonymous NC_000023.11:g.154999522C>T NC_000023.10:g.154227797C>T NG_011403.2:g.28202G>A LRG_555:g.28202G>A LRG_555t1:c.222G>A LRG_555p1:p.Thr74= - Protein change
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- Other names
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- Canonical SPDI
- NC_000023.11:154999521: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.
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The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD) 0.00012
- Links
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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F8 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
958 | 1234 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 31, 2022 | RCV000756113.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 19, 2023 | RCV003489853.1 | |
F8-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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May 17, 2024 | RCV004745577.1 |
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
(Jan 11, 2018)
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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: SCV000883831.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The F8 c.222G>A; p.Thr74Thr variant is reported in one patient presenting with mild hemophilia A and low FVIII levels (FVIII:48%) (Martorell 2015). mRNA analysis showed … (more)
The F8 c.222G>A; p.Thr74Thr variant is reported in one patient presenting with mild hemophilia A and low FVIII levels (FVIII:48%) (Martorell 2015). mRNA analysis showed two bands of different sizes (1012bp and 890 bp), with the smaller resulting from exon 2 skipping which causes a frameshift and early termination codon (Martorell 2015).This variant is found in the general population with a low overall allele frequency of 0.001% (2 out of 200420 alleles) in the Genome Aggregation Database. This variant is a synonymous substitution in exon 2, where the codon change (ACG to ACA) does not alter the protein sequence. However, in support of the functional data, computational algorithms (SpliceSiteFinder-like, MaxEntScan, NNSplice, GeneSplicer, Human Splicing Finder) predict this variant creates a cryptic splice acceptor site and may impact splicing. Based on the above information, this variant is considered likely pathogenic. References: Martorell L et al. Molecular characterization of ten F8 splicing mutations in RNA isolated from patient's leucocytes: assessment of in silico prediction tools accuracy. Haemophilia. 2015 Mar;21(2):249-57. (less)
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Uncertain significance
(Jan 31, 2022)
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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: SCV002562585.2
First in ClinVar: Aug 23, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies are inconsistent as to whether the variant affects splicing (Zimmermann MA et al., 2013; Martorell L et al., 2015; Jourdy Y et … (more)
Published functional studies are inconsistent as to whether the variant affects splicing (Zimmermann MA et al., 2013; Martorell L et al., 2015; Jourdy Y et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30690819, 23088352, 25652415, 29296726, 26245874) (less)
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Uncertain significance
(Dec 19, 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: SCV004241320.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: F8 c.222G>A alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. … (more)
Variant summary: F8 c.222G>A alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, several publications report experimental evidence with conflicting results on whether this variant affects mRNA splicing. One publication reports that the variant leads to the production of a combination of wild-type transcripts and transcripts lacking exon 2, leading to the introduction of a premature termination codon (Martorell_2015). Conversely, two other publications report that the variant results in no aberrant splicing in both patient-derived cDNA and a minigene splicing assay (Zimmerman_2013, Jourdy_2019). The variant allele was found at a frequency of 1.4e-05 in 1206490 control chromosomes (i.e., 17 alleles including 5 hemizygotes; gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in F8 causing Factor VIII Deficiency (Hemophilia A) (1.4e-05 vs 0.0098), allowing no conclusion about variant significance. c.222G>A has been reported in the literature in individuals affected with Hemophilia A, often in association with a mild phenotype (e.g., Bernardo_2022, Johnsen_2022, Kingsmore_2022, Martorell_2015, Zimmerman_2013, Jourdy_2019). The variant has also been reported in carriers not affected with Hemophilia A (e.g., Batlle_2016). These reports therefore do not provide unequivocal conclusions about association of the variant with Factor VIII Deficiency (Hemophilia A). The following publications have been ascertained in the context of this evaluation (PMID: 26245874, 35743412, 35770352, 30690819, 36007526, 25652415, 23088352).Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(May 17, 2024)
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no assertion criteria provided
Method: clinical testing
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F8-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005359127.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The F8 c.222G>A is a noncoding alteration. This variant has been reported in individuals with mild Hemophilia A (Zimmermann et al. 2013. PubMed ID: 23088352; … (more)
The F8 c.222G>A is a noncoding alteration. This variant has been reported in individuals with mild Hemophilia A (Zimmermann et al. 2013. PubMed ID: 23088352; Martorell et al. 2015. PubMed ID: 25652415; Jourdy et al. 2019. PubMed ID: 30690819). However, functional studies showed conflicting results: no effect on mRNA splicing was reported in Zimmermann et al. and Jourdy et al’s studies, whereas partial mRNA skipping was described by Martorell et al. (Zimmermann et al. 2013. PubMed ID: 23088352; Martorell et al. 2015. PubMed ID: 25652415; Jourdy et al. 2019. PubMed ID: 30690819). This variant is reported in 0.0022% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, 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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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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A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases. | Kingsmore SF | American journal of human genetics | 2022 | PMID: 36007526 |
Results of genetic analysis of 11 341 participants enrolled in the My Life, Our Future hemophilia genotyping initiative in the United States. | Johnsen JM | Journal of thrombosis and haemostasis : JTH | 2022 | PMID: 35770352 |
Applicability of the Thrombin Generation Test to Evaluate the Hemostatic Status of Hemophilia A Patients in Daily Clinical Practice. | Bernardo Á | Journal of clinical medicine | 2022 | PMID: 35743412 |
Splicing analysis of 26 F8 nucleotide variations using a minigene assay. | Jourdy Y | Haemophilia : the official journal of the World Federation of Hemophilia | 2019 | PMID: 30690819 |
Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): Proposal for a new diagnostic paradigm. | Batlle J | Thrombosis and haemostasis | 2016 | PMID: 26245874 |
Molecular characterization of ten F8 splicing mutations in RNA isolated from patient's leucocytes: assessment of in silico prediction tools accuracy. | Martorell L | Haemophilia : the official journal of the World Federation of Hemophilia | 2015 | PMID: 25652415 |
Analysis of F8 mRNA in haemophilia A patients with silent mutations or presumptive splice site mutations. | Zimmermann MA | Haemophilia : the official journal of the World Federation of Hemophilia | 2013 | PMID: 23088352 |
Text-mined citations for rs1232517683 ...
HelpRecord last updated Oct 13, 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.