NM_000132.4(F8):c.4828G>T (p.Ala1610Ser) AND Hereditary factor VIII deficiency disease

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 19, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002471263.1

Allele description [Variation Report for NM_000132.4(F8):c.4828G>T (p.Ala1610Ser)]

NM_000132.4(F8):c.4828G>T (p.Ala1610Ser)

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.4828G>T (p.Ala1610Ser)

HGVS:

NC_000023.11:g.154928962C>A
NG_011403.2:g.98762G>T
NM_000132.4:c.4828G>TMANE SELECT
NP_000123.1:p.Ala1610Ser
LRG_555t1:c.4828G>T
LRG_555:g.98762G>T
LRG_555p1:p.Ala1610Ser
NC_000023.10:g.154157237C>A
NM_000132.3:c.4828G>T

Protein change:

A1610S

Links:

dbSNP: rs782127226

NCBI 1000 Genomes Browser:

rs782127226

Molecular consequence:

NM_000132.4:c.4828G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002768924	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 19, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8639447, 21645226, 24108539, 28252515, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002768924

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 19, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular characterization of haemophilia A in southern Chinese.

Chan V, Pang A, Chan TP, Chan VW, Chan TK.

Br J Haematol. 1996 May;93(2):451-6.

PubMed [citation]

PMID:: 8639447

Most factor VIII B domain missense mutations are unlikely to be causative mutations for severe hemophilia A: implications for genotyping.

Ogata K, Selvaraj SR, Miao HZ, Pipe SW.

J Thromb Haemost. 2011 Jun;9(6):1183-90. doi: 10.1111/j.1538-7836.2011.04268.x.

PubMed [citation]

PMID:: 21645226
PMCID:: PMC3111924

See all PubMed Citations (5)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768924.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3A-VUS Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Hemophilia A (MIM#306700). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 6 heterozygotes, 0 homozygotes, 2 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated B domain (PMID: 24108539). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ala1610Pro) has been reported in a single case of Hemophilia A (MIM#306700). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual with Hemophilia A (MIM#306700) described to have had moderate deficiency in the original report but later described as severe in EAHAD database (PMID: 8639447, https://dbs.eahad.org/). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is conflicting. Due to the different cell lines used, enzymatic activity and antigen secretion were either reduced or no differences were observed compared to wild-type protein (PMID: 24108539, 21645226). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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