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]

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Variant: NM_001754.4(RUNX1):c.205G>C (p.Gly69Arg)

CA10014569

463990 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8ea17be0-3ed0-4d8a-b328-0a6493331461

Approved on: 2021-01-11

Published on: 2021-01-11

HGVS expressions

NM_001754.4:c.205G>C

NM_001754.4(RUNX1):c.205G>C (p.Gly69Arg)

NM_001001890.2:c.124G>C

NM_001122607.1:c.124G>C

NM_001001890.3:c.124G>C

NM_001122607.2:c.124G>C

NM_001754.5:c.205G>C

ENST00000300305.7:c.205G>C

ENST00000344691.8:c.124G>C

ENST00000358356.9:c.124G>C

ENST00000399237.6:c.169G>C

ENST00000399240.5:c.124G>C

ENST00000437180.5:c.205G>C

ENST00000455571.5:c.166G>C

ENST00000482318.5:c.59-6276G>C

NC_000021.9:g.34886989C>G

CM000683.2:g.34886989C>G

NC_000021.8:g.36259286C>G

CM000683.1:g.36259286C>G

NC_000021.7:g.35181156C>G

NG_011402.2:g.1102723G>C

Benign

BS1 BS3

BA1 BP4 BP2 BP7 BS4 PVS1 PP3 PP1 PM5 PM4 PM1 PM2 PM6 PS1 PS3 PS4

Evidence Links 2

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The NM_001754.4:c.205G>C variant that results in a Gly69Arg missense change has an MAF of 0.0003133 (0.03%, 6/19148 alleles) in the East Asian subpopulation of the gnomAD v2.1.1 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). Transactivation assays demonstrate normal transactivation as wild-type and normal DNA binding (BS3; PMIDs: 23817177 & 12393679). The variant has not been reported in the germ line of patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BS3.

BS1

The variant is reported at a frequency of 0.0003133 (6/19148 East Asian alleles) in gnomAD v2.1.1 and at a frequency of 0.0009572 (3/3134 East Asian alleles) in gnomAD v3. The gnomAD v2 frequency meets criteria for BS1; threshold: >0.00015

BS3

Evidence from PMID: 23817177 and PMID: 12393679 meet criteria for BS3.

Luciferase assay in HeLa cells demonstrated that the variant induced promoter activity similar to wild-type (Fig 3A) and DNA-binding ability in EMSA on nuclear extracts from COS-7 cells was similar or enhanced compared to wild-type (Fig 2A). Experiment included Arg204Gln (pathogenic control). PubMed:12393679

Luciferase reporter assay in U937 cells showed normal transactivation (Figure 4) and EMSA in COS7 cells showed normal DNA binding (Figure 2). Experiment included Arg201Gln (pathogenic control). PubMed:23817177

BA1

Meets BS1

BP4

The variant has a REVEL score of 0.559; threshold: <0.15

BP2

N/A

BP7

N/A

BS4

No data currently available

PVS1

N/A

PP3

The variant has a REVEL score of 0.559; threshold: >0.75

PP1

No data currently available

PM5

No data currently available

PM4

N/A

PM1

N/A

PM2

Meets BS1

PM6

No data currently available

PS1

No data currently available

PS3

Meets BS3

PS4

The variant has not been reported in the germ line of patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. It has been reported as a somatic variant, with no clinical significance. (PMID: 12393679 reports the variant in two patients with radiation-associated and therapy-related MDS/AML).

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