Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001754.5(RUNX1):c.227G>A (p.Arg76His)

CA10014566

1421576 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: bcd5de77-919e-4b52-a402-3fbd72467689
Approved on: 2024-09-25
Published on: 2024-09-25

HGVS expressions

NM_001754.5:c.227G>A
NM_001754.5(RUNX1):c.227G>A (p.Arg76His)
NC_000021.9:g.34886967C>T
CM000683.2:g.34886967C>T
NC_000021.8:g.36259264C>T
CM000683.1:g.36259264C>T
NC_000021.7:g.35181134C>T
NG_011402.2:g.1102745G>A
ENST00000675419.1:c.227G>A
ENST00000300305.7:c.227G>A
ENST00000344691.8:c.146G>A
ENST00000358356.9:c.146G>A
ENST00000399237.6:c.191G>A
ENST00000399240.5:c.146G>A
ENST00000437180.5:c.227G>A
ENST00000455571.5:c.188G>A
ENST00000482318.5:c.59-6254G>A
NM_001001890.2:c.146G>A
NM_001122607.1:c.146G>A
NM_001754.4:c.227G>A
NM_001001890.3:c.146G>A
NM_001122607.2:c.146G>A

Uncertain Significance

Met criteria codes 2
PP3 BS3_Supporting
Not Met criteria codes 24
PS2 PS4 PS3 PS1 PVS1 PP4 PP1 PP2 PM6 PM2 PM3 PM1 PM4 PM5 BA1 BS4 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.227G>A (p.Arg76His) is a missense variant with a REVEL score ≥ 0.88 (0.92) (PP3). In Koh et al 2013, they measured transcriptional activity by Luciferase reporter assay and showed a subnormal activity (>80% compared to WT) (BS3_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, BS3_Supporting.
Met criteria codes
PP3
This missense variant has a REVEL score ≥ 0.88 (0.92) (PP3).
BS3_Supporting
In Koh et al 2013, they measured transcriptional activity by Luciferase reporter assay and showed a subnormal activity (>80% compared to WT) (Figure 4). They also used an In vitro ubiquitylation assay that showed no significant impact of this variant (Figure 5).
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Variant present in gnomAD and reported only once in a AML pediatric patient (PMID: 12874780).
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest population minor allele frequency is 0.00005593 (1/17880 alleles) in East Asian population in gnomAD v2.1.1 and 0.00008326 (3/36030 alleles) in East Asian in population in gnomAD v3.1.2.
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
This variant does not reside within a region of RUNX1 that is defined as a mutational hotspot or critical functional domain by the ClinGen MMVCEP.
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
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
BS2
NA
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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