NM_000132.4(F8):c.6304G>A (p.Gly2102Ser) AND Hereditary factor VIII deficiency disease

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Mar 17, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001169186.2

Allele description [Variation Report for NM_000132.4(F8):c.6304G>A (p.Gly2102Ser)]

NM_000132.4(F8):c.6304G>A (p.Gly2102Ser)

Gene:
F8:coagulation factor VIII [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq28
Genomic location:
Preferred name:
NM_000132.4(F8):c.6304G>A (p.Gly2102Ser)
HGVS:
  • NC_000023.11:g.154896202C>T
  • NG_011403.1:g.131522G>A
  • NM_000132.4:c.6304G>AMANE SELECT
  • NP_000123.1:p.Gly2102Ser
  • LRG_555t1:c.6304G>A
  • LRG_555p1:p.Gly2102Ser
  • NC_000023.10:g.154124477C>T
  • NM_000132.3:c.6304G>A
Protein change:
G2102S
Links:
Molecular consequence:
  • NM_000132.4:c.6304G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary factor VIII deficiency disease (HEMA)
Synonyms:
Hemophilia A; Hemophilia A, congenital; Hemophilia, classic; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0010602; MedGen: C0019069; Orphanet: 98878; OMIM: 306700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001331854Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jan 13, 2018)
germlineclinical testing

Citation Link,

SCV001474163ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Mar 17, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV001331854.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001474163.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The F8 c.6304G>A; p.Gly2102Ser variant (rs200433372), also known as Gly2083Ser, is reported in the literature in individuals affected with reportedly mild hemophilia A (Debeljak 2012). This variant is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 2102 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Additionally, another variant at this codon (c.6205G>C; p.Gly2102Asp) has been reported in individuals with mild hemophilia A (Rydz 2013), and several missense variants in the same C1 domain are associated with mild hemophilia A (Green 2008, Johnsen 2017). Based on available information, the p.Gly2102Ser variant is considered to be likely pathogenic. References: Debeljak M et al. Spectrum of F8 gene mutations in haemophilia A patients from Slovenia. Haemophilia. 2012 Nov;18(6):e420-3. Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008 Oct;143(1):115-28. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. Rydz N et al. The Canadian "National Program for hemophilia mutation testing" database: a ten-year review. Am J Hematol. 2013 Dec;88(12):1030-4.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 16, 2021

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