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_001754.4(RUNX1):c.484A>G (p.Arg162Gly)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

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

Approved on: 2021-01-12

Published on: 2021-01-12

HGVS expressions

NM_001754.4:c.484A>G

NM_001754.4(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_001001890.3:c.403A>G

NM_001122607.2:c.403A>G

NM_001754.5:c.484A>G

Likely Pathogenic

PS3_Moderate PP3 PM2 PM1

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

Evidence Links 7

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

This missense variant has not been reported in gnomAD (v2 and v3) [PM2]. It has been reported as a germline variant in an unaffected proband (30s) who had a suggestive family history, including thrombocytopenia and AML (SCV001375396.1); however, all other reports of the variant are not clearly germline (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 30373888, 31649132, 32045476, 32208489). The variant is located at 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]. The variant also demonstrates reduced DNA-binding and CBFβ-binding (PMID: 17290219), as well as impaired erythropoeisis (PMID: 17234761, 21725049) [PS3_moderate], which is in line with computational evidence [PP3]. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3_moderate, PM1, PM2, and PP3.

PS3_Moderate

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

PP3

REVEL score=0.885, which is >0.75 threshold.

PM2

Absent from gnomAD with a mean coverage of at least 20X (v2 and v3).

PM1

Located at a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is defined a hotspot (PMID: 31648317, 27294619, 23958918).

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

"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

“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

“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

“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

"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 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

BP4

REVEL score=0.885, which is >0.75 threshold.

BP3

Not applicable

BP1

Not applicable

BP2