VCV000012061.33 - ClinVar

NM_000504.4(F10):c.424G>A (p.Glu142Lys)

Germline

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.

(11)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000504.4(F10):c.424G>A (p.Glu142Lys)

Variation ID: 12061 Accession: VCV000012061.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q34 13: 113140972 (GRCh38) [ NCBI UCSC ] 13: 113795286 (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	Aug 2, 2015	Oct 20, 2024	Sep 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000504.4:c.424G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000495.1:p.Glu142Lys	missense
NM_001312674.2:c.370+1502G>A		intron variant
NM_001312675.2:c.424G>A	NP_001299604.1:p.Glu142Lys	missense
NC_000013.11:g.113140972G>A
NC_000013.10:g.113795286G>A
NG_009258.1:g.23174G>A
LRG_548:g.23174G>A
LRG_548t1:c.424G>A	LRG_548p1:p.Glu142Lys
	P00742:p.Glu142Lys

... more HGVS ... less HGVS

Protein change

E142K

Other names

F10, GLU102LYS
E102K

Canonical SPDI

NC_000013.11:113140971:G:A

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.

0.00140 (A)

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

1000 Genomes Project 30x 0.00125

1000 Genomes Project 0.00140

Trans-Omics for Precision Medicine (TOPMed) 0.00185

The Genome Aggregation Database (gnomAD) 0.00347

The Genome Aggregation Database (gnomAD), exomes 0.00445

Exome Aggregation Consortium (ExAC) 0.00451

Links

UniProtKB: P00742#VAR_065434 OMIM: 613872.0007 dbSNP: rs61753266 ClinGen: CA121843 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.
F10		-	-	GRCh38 GRCh37	110	275

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.
Factor X deficiency	Uncertain significance (2)	criteria provided, single submitter	Apr 27, 2017	RCV000012841.10
not specified	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Sep 12, 2023	RCV000602474.2
Abnormal bleeding	Uncertain significance (1)	criteria provided, single submitter	Feb 1, 2019	RCV000852124.1
not provided	Likely benign (3)	criteria provided, single submitter	Jul 1, 2023	RCV001091746.18
Hereditary factor X deficiency disease	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2019	RCV001375846.4
F10-related disorder	Likely benign (1)	no assertion criteria provided	Jan 6, 2022	RCV003924826.2

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.
Likely benign (Nov 16, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000730666.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	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)
Uncertain significance (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary factor X deficiency disease Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Study: ThromboGenomics Accession: SCV000899731.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019	Publications: PubMed (1) PubMed: 31064749 Sex: male Ethnicity/Population group: European
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary factor X deficiency disease Affected status: yes Allele origin: germline	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002499582.2 First in ClinVar: Apr 23, 2022 Last updated: Sep 10, 2022 Comment: Submitted to GoldVariant by Kathleen Freson, Center for Molecular and Vascular Biology, Leuven, Belgium	Observation 1: Clinical Features: Prolonged PT and normal APTT (present) , Low Factor X (present) , Absent bleeding (present) Observation 2: Clinical Features: Bleeding (present)
Uncertain significance (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Abnormal bleeding Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Study: ThromboGenomics Accession: SCV000899732.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019	Publications: PubMed (1) PubMed: 31064749
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hereditary factor X deficiency disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001271113.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 26879396‚ 25582404‚ 7669671 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely Benign (Sep 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848138.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Glu142Lys (previously reported as Glu102Lys) variant in F10 is classified as likely benign because it has been identified in 1.8% (200/10624) of European chromosomes … (more) The p.Glu142Lys (previously reported as Glu102Lys) variant in F10 is classified as likely benign because it has been identified in 1.8% (200/10624) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org v.3.1.2), including 2 homozygotes. This variant has been reported in individuals with factor X deficiency, but it has been found alongside other homozygous variants (Marchetti 1995 PMID: 7669671, Forberg 2000 PMID: 10739379, Bastida 2016 PMID: 26879396, Downes 2019 PMID: 31064749). In vitro functional studies show that this variant retains function similar to wild type, however, may have a slight reduction as it has not been studied in isolation. This reduction is thought to be below the clinical threshold for disease (Forberg 2000 PMID: 10739379); however, these types of assays may not accurately represent biological function. ACMG/AMP criteria applied: BS1, BS3_Supporting. (less)
Likely benign (Jul 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247952.20 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: F10: BS2 Number of individuals with the variant: 1
Pathogenic (Aug 01, 1995)	no assertion criteria provided Method: literature only	FACTOR X DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033081.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 02, 2015	Publications: PubMed (1) PubMed: 7669671 Comment on evidence: For discussion of the glu102-to-lys (E102K) mutation in the F10 gene that was found in compound heterozygous state in a patient with factor X deficiency … (more) For discussion of the glu102-to-lys (E102K) mutation in the F10 gene that was found in compound heterozygous state in a patient with factor X deficiency (227600) by Marchetti et al. (1995), see 613872.0006. (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001963273.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Likely benign (Jan 06, 2022)	no assertion criteria provided Method: clinical testing	F10-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004737428.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972895.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
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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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

The p.Glu142Lys (previously reported as Glu102Lys) variant in F10 is classified as likely benign because it has been identified in 1.8% (200/10624) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org v.3.1.2), including 2 homozygotes. This variant has been reported in individuals with factor X deficiency, but it has been found alongside other homozygous variants (Marchetti 1995 PMID: 7669671, Forberg 2000 PMID: 10739379, Bastida 2016 PMID: 26879396, Downes 2019 PMID: 31064749). In vitro functional studies show that this variant retains function similar to wild type, however, may have a slight reduction as it has not been studied in isolation. This reduction is thought to be below the clinical threshold for disease (Forberg 2000 PMID: 10739379); however, these types of assays may not accurately represent biological function. ACMG/AMP criteria applied: BS1, BS3_Supporting.

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
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.	Downes K	Blood	2019	PMID: 31064749
Design and application of a 23-gene panel by next-generation sequencing for inherited coagulation bleeding disorders.	Bastida JM	Haemophilia : the official journal of the World Federation of Hemophilia	2016	PMID: 26879396
Congenital combined deficiency of coagulation factors VII and X--different genetic mechanisms.	Pavlova A	Haemophilia : the official journal of the World Federation of Hemophilia	2015	PMID: 25582404
Molecular bases of CRM+ factor X deficiency: a frequent mutation (Ser334Pro) in the catalytic domain and a substitution (Glu102Lys) in the second EGF-like domain.	Marchetti G	British journal of haematology	1995	PMID: 7669671

Text-mined citations for rs61753266 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000504.4(F10):c.424G>A (p.Glu142Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61753266 ...