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]
  • See Evidence submitted by expert panel for details.

Variant: NM_001754.4(RUNX1):c.486G>T (p.Arg162Ser)

CA16602488

376019 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4df11a8a-66b6-4bf1-9ad2-b1edf5add537
Approved on: 2021-01-12
Published on: 2021-01-12

HGVS expressions

NM_001754.4:c.486G>T
NM_001754.4(RUNX1):c.486G>T (p.Arg162Ser)
NC_000021.9:g.34880579C>A
CM000683.2:g.34880579C>A
NC_000021.8:g.36252876C>A
CM000683.1:g.36252876C>A
NC_000021.7:g.35174746C>A
NG_011402.2:g.1109133G>T
ENST00000675419.1:c.486G>T
ENST00000300305.7:c.486G>T
ENST00000344691.8:c.405G>T
ENST00000358356.9:c.405G>T
ENST00000399237.6:c.450G>T
ENST00000399240.5:c.405G>T
ENST00000437180.5:c.486G>T
ENST00000482318.5:c.*76G>T
NM_001001890.2:c.405G>T
NM_001122607.1:c.405G>T
NM_001001890.3:c.405G>T
NM_001122607.2:c.405G>T
NM_001754.5:c.486G>T
More

Likely Pathogenic

Met criteria codes 4
PP3 PM2 PM1 PM5_Supporting
Not Met criteria codes 22
BP5 BP7 BP4 BP3 BP1 BP2 PS1 PS2 PS3 PS4 BA1 PP1 PP2 PP4 PM6 PM3 PM4 PVS1 BS1 BS4 BS3 BS2

Evidence Links 7

Expert Panel

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]. Although it has not been clearly reported as a germline variant (PMID: 28855357, 28927163, 31649132, COSMIC), it 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) [PM1]. Although this variant has not been functionally evaluated, computational evidence supports a deleterious effect of this variant [PP3] and another missense variant at the same residue (i.e. p.R162G) is classified as likely pathogenic by the ClinGen MM-VCEP [PM5_supporting]. 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: PM1, PM2, PM5_supporting, and PP3.
Met criteria codes
PP3
REVEL score=0.818, which is >0.75 threshold. SSF and MES show loss of a putative cryptic donor splice site at c.485.
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).
“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
“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
"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
"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
“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
PM5_Supporting
R162G is classified as likely pathogenic by the ClinGen MM-VCEP.
Not Met criteria codes
BP5
Not applicable
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
REVEL score=0.818, which is >0.75 threshold.
BP3
Not applicable
BP1
Not applicable
BP2
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
While there are reports of this variant in patients with hematological neoplasm, either the cDNA is unknown, germline origin is unknown, or somatic status has been confirmed (PMID: 28855357, 28927163, 31649132, COSMIC).
BA1
Absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
Not applicable
PP4
Not applicable
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
Not applicable
PM4
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
BS1
Absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
BS4
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
BS2
Not applicable
Curation History
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