Evidence Repository - Clinical Genome Resources

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Variant: NM_001754.5(RUNX1):c.484A>G (p.Arg162Gly)

CA16602491

376022 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2912edeb-f11c-4523-87b7-fb8694197de1

HGVS expressions

NM_001754.5:c.484A>G

NM_001754.5(RUNX1):c.484A>G (p.Arg162Gly)

NC_000021.9:g.34880581T>C

CM000683.2:g.34880581T>C

NC_000021.8:g.36252878T>C

CM000683.1:g.36252878T>C

NC_000021.7:g.35174748T>C

NG_011402.2:g.1109131A>G

ENST00000675419.1:c.484A>G

ENST00000300305.7:c.484A>G

ENST00000344691.8:c.403A>G

ENST00000358356.9:c.403A>G

ENST00000399237.6:c.448A>G

ENST00000399240.5:c.403A>G

ENST00000437180.5:c.484A>G

ENST00000482318.5:c.*74A>G

NM_001001890.2:c.403A>G

NM_001122607.1:c.403A>G

NM_001754.4:c.484A>G

NM_001001890.3:c.403A>G

NM_001122607.2:c.403A>G

Pathogenic

PM5_Supporting PS3_Moderate PP1 PP3 PM2_Supporting PM1 PS4_Supporting

PVS1 BS2 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS1 PS2 BA1 PP4 PP2 PM3 PM4 PM6

Evidence Links 7

Expert Panel

Myeloid Malignancy VCEP

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

The c.484A>G variant in RUNX1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 162 (p.R162G), which is a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is considered a hotspot residue (PMID: 31648317, 27294619, 23958918), especially from a somatic perspective (PMID: 32208489) (PM1). This variant is absent from gnomAD v2 and v3 (PM2_Supporting), and has been reported in a proband meeting RUNX1-phenotypic criteria: history of bruising, menorrhagia, anemia, and a platelet defect with atypical platelet function tests, abnormal electron microscopy study, and atypical macrophages on bone marrow biopsy (PS4_Supporting; SCV001375396.1 and National Human Genome Research Institute). In addition, her older son (non-carrier) is unaffected, her younger son (carrier) has a history of thrombocytopenia (easy bleeding and bruising), frequent epistaxis, petechiae at 9 months, and an abnormal platelet electron microscopy study, and her mother (carrier) was diagnosed with AML at 45 (BMT done) and has a history of easy bleeding (PP1; National Human Genome Research Institute); finally, there is a supportive family history of AML in deceased relatives. Note that all other reports of the variant are not clearly germline (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 30373888, 31649132, 32045476, 32208489). Functionally, the variant demonstrates reduced DNA-binding and CBFβ-binding (PMID: 17290219), as well as impaired erythropoiesis (PMID: 17234761, 21725049 (PS3_Moderate), which is in line with computational evidence (REVEL score of 0.885 ≥ 0.88 threshold; PP3). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3_Moderate, PS4_Supporting, PM1, PM2_Supporting, PP1, and PP3.

PM5_Supporting

This variant is a missense change at the same residue (p.R162) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 376020, 376019, 376021) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting).

PS3_Moderate

R135G demonstrates reduced DNA-binding and CBFβ-binding (PMID: 17290219), as well as impaired erythropoeisis (PMID: 17234761, 21725049).

PP1

Relatives of the proband cited in this curation (SCV001375396.1) are carriers and affected: her younger son has a history of thrombocytopenia (easy bleeding and bruising), frequent epistaxis, petechiae at 9 months, and an abnormal platelet electron microscopy study, and her mother was diagnosed with AML at 45 (BMT done) and has a history of easy bleeding; in addition, her older son is unaffected and a non-carrier. Finally, there is a suspicious family history in deceased relatives (maternal grandmother with bruising and brain bleed, a maternal great-uncle and his daughter with AML, a maternal great-uncle with AML twice and a son with unspecified but likely related symptoms). (National Human Genome Research Institute)

PP3

This missense variant has a REVEL score ≥ 0.88 (0.885) (PP3).

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).

PM1

This variant affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1).

"The mutations occurring in these residues, such as R80C, R80G, K83Q, K83R, R135K, R135S, R139Q, R139L, D171Y, D171G, and R174Q detected in this study, would result in loss of hydrogen bonding interaction to DNA or disruption of the folding architecture of RUNX1; additional S114P and S114W were supposed to abolish heterodimerization with CBF-β.39" However, the cited article (PMID: 11257229) does not include this variant in its evaluation." PubMed:19808697

“In addition, four amino acids located on β9, L9, and β12, including Arg135, Arg139, Gly143, and Lys167 (Arg135 is not shown in Figure 3A for clarity), make direct contacts with the DNA backbone 29, 30… When anchored on the DNA helix, the three “sequence-specific” loops are maintained by “in-line” van der Waals interactions from Pro173 via His78 and Lys167 to the backbone of L9 as well as by a nearly linear array of salt bridge and attractive interactions of the type CH3…O and CH3…NH2 formed by Arg174, Asp171, Val170, and Arg139 (shown in Figure 3A)... Disease-related mutations in amino acids that form nonspecific contacts with the DNA backbone, Arg135Gly [43], Arg139Gln 37, 41, and Arg139Gly [42], should also be attributed to the loss of interactions that support protein loops (L3 by Arg135 and L9 by Arg139) at the protein-DNA interface Figure 3, Figure 4.” PubMed:12377125

“In Runx1, Arg135 and Arg139 interact with G105–A107 and G4–C6, respectively (green), while Arg80 interacts with A106–T107, and Lys83 interacts with T107, T109, and A7 (yellow).” PubMed:28231333

“Ten of these amino acids (Arg-80, Lys-83, Arg-135, Arg-139, Arg-142, Lys-167, Thr-169, Asp-171, Arg-174, and Arg-177) were shown in the crystal structures of the RD-CBFβ-DNA ternary complex to make side chain contacts to the DNA bases or the phosphate backbone (45, 47).” PubMed:12807882

“DNA binding is mediated by 3 loops called loop(βA'-B), loop(βE'-F), and C-terminal tail in the runt domain, and the amino acid residues (Arg80, Lys83, Thr84, Arg135, Arg139, Gly141, Arg142, Gly143, Ile168, Thr169, Val170, Asp171, Arg174, and Arg177) that directly contact the DNA were determined. Half of these residues (Arg80, Lys83, Arg135, Arg139, Asp171, Arg174, and Arg177) were found to be the targets of amino acid replacement by missense mutations in de novo MDS/AML and/or FPD/AML pedigrees in previous reports." PubMed:12393679

"At the 5′ end of the consensus-binding site, strand βE′ (Arg 135) and loop βA′–B (Lys 83 and Thr 84) contact the phosphate backbone of DNA strand E (T2, T3 and G4) (Fig. 2a)." PubMed:11276260

A computational tool, Hotspot3D, identified a spatial hotspot cluster in RUNX1 that includes Arg162. PubMed:27294619

PS4_Supporting

A proband (tested in her 30s) has a history of bruising, menorrhagia, anemia, and a platelet defect (with atypical platelet function tests, abnormal electron microscopy study, and atypical macrophages on bone marrow biopsy) and a family history of thrombocytopenia and AML (SCV001375396.1 and National Human Genome Research Institute). Otherwise, there are reports of this variant in patients with hematological neoplasm, but either somatic status has been confirmed or germline origin is unknown (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 30373888, 31649132, 32045476, 32208489). Furthermore, R162K has been considered one of the most recurrent somatic missense variants in sporadic AML based on not being observed in a cohort with 103 germline SNV (p<0.05) (PMID: 32208489).

PVS1

This variant is not a null variant.

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

Segregation was not found to be absent in two or more informative meiosis.

BS1

This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.

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.

BP3

This rule is not applicable for MM-VCEP.

BP4

This missense variant does not have a REVEL score < 0.50.

BP1

This rule is not applicable for MM-VCEP.

BP5

This rule is not applicable for MM-VCEP.

BP7

This variant is not a synonymous or intronic variant.

PS1

There has not yet been a missense change resulting in the same change in protein which has been determined to be pathogenic at this amino acid residue.

PS2

De novo data for this variant has not been reported in literature.

BA1

This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.

PP4

This rule is not applicable for MM-VCEP.

PP2

This rule is not applicable for MM-VCEP.

PM3

This rule is not applicable for MM-VCEP.

PM4

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

PM6

De novo data for this variant has not been reported in literature.

Approved on: 2024-03-26

Published on: 2024-03-26

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