NM_000133.4(F9):c.316G>A (p.Gly106Ser) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 29, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001810846.14

Allele description [Variation Report for NM_000133.4(F9):c.316G>A (p.Gly106Ser)]

NM_000133.4(F9):c.316G>A (p.Gly106Ser)

Gene:

F9:coagulation factor IX [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq27.1

Genomic location:

Preferred name:

NM_000133.4(F9):c.316G>A (p.Gly106Ser)

Other names:

F9, GLY60SER; G60S; NM_000133.3(F9):c.316G>A

HGVS:

NC_000023.11:g.139541114G>A
NG_007994.1:g.15379G>A
NM_000133.4:c.316G>AMANE SELECT
NM_001313913.2:c.277+3728G>A
NP_000124.1:p.Gly106Ser
NP_000124.1:p.Gly106Ser
LRG_556t1:c.316G>A
LRG_556:g.15379G>A
LRG_556p1:p.Gly106Ser
NC_000023.10:g.138623273G>A
NM_000133.3:c.316G>A
P00740:p.Gly106Ser

Protein change:

G106S; GLY60SER

Links:

UniProtKB: P00740#VAR_006549; OMIM: 300746.0022; dbSNP: rs137852233

NCBI 1000 Genomes Browser:

rs137852233

Molecular consequence:

NM_001313913.2:c.277+3728G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000133.4:c.316G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000603535	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Sep 17, 2021)	germline	clinical testing	Citation Link,
SCV004225499	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 29, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000603535

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Pathogenic
(Sep 17, 2021)

germline

clinical testing

Citation Link,

SCV004225499

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 29, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	5	not provided	not provided	not provided	not provided	clinical testing

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, SCV000603535.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The F9 c.316G>A; p.Gly106Ser variant (rs1378522233), also known as Gly60Ser or FIX Durham, is reported in numerous patients diagnosed with mild hemophilia B (Chavali 2009, Chen 1989, Denton 1988, Poort 1989, Factor IX Variant Database and references therein). This variant is reported as pathogenic in ClinVar (Variation ID: 10579) and is found in the general population at a low overall allele frequency of 0.003% (5/204867 alleles, including 3 hemizygotes) in the Genome Aggregation Database. The glycine at codon 106 is highly conserved and located in the calcium-binding EGF-like domain. Structural analyses demonstrate that the variant increases the likelihood of defective folding in the EGF-like domain of the protein (Whiteman 1998). Additionally, other amino acid substitutions at this codon (Arg, Cys, and Asp) have been reported in individuals with hemophilia B and are considered disease-causing (Factor IX Variant Database and references therein). Based on available information, the p.Gly106Ser variant is considered to be pathogenic. References: Factor IX Variant Database: http://f9-db.eahad.org/ Chavali S et al. Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. Genomics. 2009 Dec;94(6):433-7. Chen SH et al. Three point mutations in the factor IX genes of five hemophilia B patients. Identification strategy using localization by altered epitopes in their hemophilic proteins. J Clin Invest. 1989 Jul;84(1):113-8. Denton PH et al. Hemophilia B Durham: a mutation in the first EGF-like domain of factor IX that is characterized by polymerase chain reaction. Blood. 1988 Oct;72(4):1407-11. Poort SR et al. A Dutch pedigree with mild hemophilia B with a missense mutation in the first EGF domain (factor IXOud en Nieuw Gastel). Nucleic Acids Res. 1989 Jul 25;17(14):5869. Whiteman P et al. A Gly --> Ser change causes defective folding in vitro of calcium-binding epidermal growth factor-like domains from factor IX and fibrillin-1. J Biol Chem. 1998 Apr 3;273(14):7807-13.

#	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

From Mayo Clinic Laboratories, Mayo Clinic, SCV004225499.1

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

Description

PP3, PP5, PM1_supporting, PM5, PS3, PS4_moderate

#	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		5	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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