Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000132.4(F8):c.6658G>C (p.Ala2220Pro)

CA10567779

1029498 (ClinVar)

Gene: F8 (HGNC:2157)

Condition: hemophilia A (MONDO:0010602)

Inheritance Mode: X-linked inheritance

UUID: f0c59eaf-6cee-4161-957b-83eb0a2a4db2

Approved on: 2025-08-15

Published on: 2025-08-21

HGVS expressions

NM_000132.4(F8):c.6658G>C (p.Ala2220Pro)

NM_000132.4:c.6658G>C

NC_000023.11:g.154861783C>G

CM000685.2:g.154861783C>G

NC_000023.10:g.154090058C>G

CM000685.1:g.154090058C>G

NC_000023.9:g.153743252C>G

NG_011403.1:g.165941G>C

NG_011403.2:g.165941G>C

ENST00000360256.9:c.6658G>C

ENST00000644698.1:c.391G>C

ENST00000330287.10:c.253G>C

ENST00000360256.8:c.6658G>C

NM_000132.3:c.6658G>C

NM_019863.2:c.253G>C

NM_019863.3:c.253G>C

Pathogenic

PP4_Moderate PM2_Supporting PP3 PP1_Moderate PS4_Very Strong

BA1 BS3 BS1

Evidence Links 0

Expert Panel

Coagulation Factor Deficiency VCEP

Criteria Specification Information

Criteria Specification: ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The NM_000132.4(F8):c.6658G>C; p.Ala2220Pro is absent in males in gnomAD database v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.713, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3). This variant has been reported in at least 17 individuals with mild/moderate hemophilia A (PMID: 18034765 ; 20536985, 10910913, 29296726), meeting the PS4_Very Strong & PP4_Moderate criteria. This variant was found to co-segregate with the disease in multiple affected family members, with 7 meioses observed in one family (PP1_Moderate; PMID: 20536985). This variant has also been associated with incidence of inhibitor development to factor replacement products (PMID: 18034765). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0: PM2_Supporting, PP3, PS4_Very Strong, PP4_Moderate, PP1_Moderate.

PP4_Moderate

1 proband with moderate hemophilia A genotyped through My Life Our Future (MLOF).

PM2_Supporting

The variant is absent in males in GnomAD database v.2.1.1 (PM2_Supporting).

PP3

The computational predictor REVEL gives a score of 0.713, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3_Supporting).

PP1_Moderate

This variant was found to segregate with the disease in multiple affected family members, with 4 meioses observed in one family (PMID: 20536985).

PS4_Very Strong

This variant has been reported in at least 17 unrelated patients with mild hemophilia A, with one proband being used for PP4 (PMID: 10910913, 29296726, 18034765, 20536985). In summary, it fits the PS4_Very strong criteria.

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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