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_001754.5(RUNX1):c.649G>A (p.Gly217Arg)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA10014385

436614 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 25c2ce1c-5117-4f09-bbbe-8ba144738c9c

Approved on: 2025-05-02

Published on: 2025-05-02

HGVS expressions

NM_001754.5:c.649G>A

NM_001754.5(RUNX1):c.649G>A (p.Gly217Arg)

NC_000021.9:g.34834566C>T

CM000683.2:g.34834566C>T

NC_000021.8:g.36206863C>T

CM000683.1:g.36206863C>T

NC_000021.7:g.35128733C>T

NG_011402.2:g.1155146G>A

ENST00000675419.1:c.649G>A

ENST00000300305.7:c.649G>A

ENST00000344691.8:c.568G>A

ENST00000358356.9:c.568G>A

ENST00000399237.6:c.613G>A

ENST00000399240.5:c.532+24908G>A

ENST00000437180.5:c.649G>A

ENST00000469087.1:n.185G>A

ENST00000482318.5:c.*239G>A

NM_001001890.2:c.568G>A

NM_001122607.1:c.568G>A

NM_001754.4:c.649G>A

NM_001001890.3:c.568G>A

NM_001122607.2:c.568G>A

Uncertain Significance

PM6 PM2 PM4 PM1 PM5 PM3 PVS1 BA1 BS2 BS3 BS4 BS1 BP3 BP2 BP4 BP1 BP7 BP5 PS3 PS1 PS2 PS4 PP4 PP1 PP3 PP2

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.649G>A (p.Gly217Arg) is a missense variant which does not meet any ACMG/AMP criteria. 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: None.

PM6

No data currently available

PM2

This variant is present in at least one population database.

PM4

This variant is not an in-frame deletion/insertion.

PM1

This variant does not affect any of the following amino acid residues, nor is it located within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 OR within residues 89-204.

PM5

Another variant at the same residue, Gly217Ala, has been curated by the MM-VCEP as VUS. Criteria for PM5 not met.

PM3

“This rule is not applicable for MM-VCEP”

PVS1

This variant is not a null variant.

BA1

MAF of 0.0001064 does not meet BA1 threshold

BS2

“This rule is not applicable for MM-VCEP”

BS3

This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing.

BS4

No data currently available

BS1

MAF of 0.0001064 (0.01%; 7/65790 alleles) in the non-Finnish European population of the gnomAD v3.1 cohort does not fall within the 0.00015 (0.015%) and 0.0015 (0.15%) range, and does not meet criteria for BS1 -gnomAD (v.4) TOTAL. 0.00466% (64/1373346) and East Asian 0.008799% (2/22730)

BP3

“This rule is not applicable for MM-VCEP”

BP2

This variant has not been observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

BP4

This missense variant has a REVEL score of 0.624 and does not meet BP4 cut-off of <0.15. SpliceAI predicts loss of acceptor site of intron 5 with a score of 0.01.

BP1

MM-VCEP deemed N/A for RUNX1

BP7

N/A

BP5

“This rule is not applicable for MM-VCEP”

PS3

This variant has not been featured in in vitro or in vivo functional studies showing a damaging effect on the gene or gene product.

PS1

N/A

PS2

No data currently available

PS4

1 proband from PMID: 29365323, with germ line (cultured fibroblasts) Gly217Arg variant and multiple myeloma and t-AML, with a family history of breast and colon cancers, meets criteria for PS4_Supporting. However, PS4 cannot be applied since 7 alleles are noted in gnomAD non-Finnish European population.

PP4

“This rule is not applicable for MM-VCEP”

PP1

PMID: 20880108 reports a family with 4 members with thrombocytopenia; however, only the proband was tested for the variant.

PP3

This missense variant has a REVEL score of 0.624 and does not meet PP3 cut-off of >0.75

PP2

MM-VCEP deemed N/A for RUNX1

Curation History

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