NM_000132.3(F8):c.5815G>C (p.Ala1939Pro) AND Hereditary factor VIII deficiency disease

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Apr 28, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001002198.2

Allele description [Variation Report for NM_000132.3(F8):c.5815G>C (p.Ala1939Pro)]

NM_000132.3(F8):c.5815G>C (p.Ala1939Pro)

Gene:
F8:coagulation factor VIII [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq28
Genomic location:
Preferred name:
NM_000132.3(F8):c.5815G>C (p.Ala1939Pro)
HGVS:
  • NC_000023.11:g.154904296C>G
  • NG_011403.1:g.123428G>C
  • NM_000132.3:c.5815G>C
  • NP_000123.1:p.Ala1939Pro
  • NC_000023.10:g.154132571C>G
Protein change:
A1939P
Links:
dbSNP: rs1603432979
NCBI 1000 Genomes Browser:
rs1603432979
Molecular consequence:
  • NM_000132.3:c.5815G>C - 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
SCV001160071ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Nov 9, 2018)
germlineclinical testing

Citation Link,

SCV001622570Center for Genomic Medicine,King Faisal Specialist Hospital and Research Centercriteria provided, single submitter
Uncertain significance
(Apr 28, 2021)
germlineresearch

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001160071.1

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

Description

The F8 c.5815G>C; p.Ala1939Pro variant, to our knowledge, is not described in the medical literature or in gene-specific databases. It is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at codon 1939 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. This variant also occurs at the last nucleotide in the exon and is predicted to weaken the nearby canonical donor splice site (Alamut v.2.11). Additional variants at this position (p.Ala1939Glu, p.Ala1939Ser, and p.Ala1939Thr) have been described in individuals affected with severe hemophilia A and are considered pathogenic (see link to F8 database and references therein). Based on available information, the p.Ala1939Pro variant is considered likely pathogenic. REFERENCES Link to F8 database: http://www.factorviii-db.org/

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

From Center for Genomic Medicine,King Faisal Specialist Hospital and Research Center, SCV001622570.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 20, 2021

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