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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001754.5(RUNX1):c.351+1G>T

CA410203333

988837 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3397bd48-d848-44cc-99b5-e9105dda8018

HGVS expressions

NM_001754.5:c.351+1G>T

NM_001754.5(RUNX1):c.351+1G>T

NC_000021.9:g.34886842C>A

CM000683.2:g.34886842C>A

NC_000021.8:g.36259139C>A

CM000683.1:g.36259139C>A

NC_000021.7:g.35181009C>A

NG_011402.2:g.1102870G>T

ENST00000675419.1:c.351+1G>T

ENST00000300305.7:c.351+1G>T

ENST00000344691.8:c.270+1G>T

ENST00000358356.9:c.270+1G>T

ENST00000399237.6:c.315+1G>T

ENST00000399240.5:c.270+1G>T

ENST00000437180.5:c.351+1G>T

ENST00000455571.5:c.312+1G>T

ENST00000482318.5:c.59-6129G>T

NM_001001890.2:c.270+1G>T

NM_001122607.1:c.270+1G>T

NM_001754.4:c.351+1G>T

NM_001001890.3:c.270+1G>T

NM_001122607.2:c.270+1G>T

Pathogenic

PVS1 PM2_Supporting PS4_Moderate

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

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. According to SpliceAI prediction, the donor loss is 0.99 at -1 bp. This variant is expected to result in exon 4 skipping, leading to a frameshift (PVS1). This variant has been reported in 2 probands (#17, and #44.2), both meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 24100448 and 32935436). This variant is completely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_moderate, PM2_supporting.

PVS1

The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. According to SpliceAI prediction, the donor loss is 0.99 at -1 bp. This variant is expected to result in exon 4 skipping, leading to a frameshift (PVS1).

PM2_Supporting

This variant is completely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting).

PS4_Moderate

This variant has been reported in 2 probands (#17, and #44.2), both meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 24100448 and 32935436).

PM3

The MMVCEP does not evaluate this rule.

PM1

This rule cannot be applied since this is a canonical splice site variant.

PM4

This rule cannot be applied since this is a canonical splice site variant.

PM5

This rule cannot be applied since this is a canonical splice site variant.

PM6

This rule cannot be applied since, to our knowledge, this information has not been provided in any study.

BA1

This rule cannot be applied since the variant is completely absent from all population databases.

BS4

This rule cannot be applied because we have no information about segregation.

BS3

BS3 cannot be applied because the variant meets PVS1.

BS1

This rule cannot be applied since the variant is completely absent from all population databases.

BS2

This rule is not applicable for MM-VCEP.

BP5

The MMVCEP does not evaluate this rule.

BP7

This rule cannot be applied since this is a canonical splice site variant.

BP2

This rule cannot be applied since, to our knowledge, this information has not been provided in any study.

BP3

The MMVCEP does not evaluate this rule.

BP4

This rule cannot be applied since this is a canonical splice site variant.

BP1

The MMVCEP does not evaluate this rule.

PS2

This rule cannot be applied since, to our knowledge, this information has not been provided in any study.

PS3

PS3 cannot be applied because the variant meets PVS1.

PS1

This rule cannot be applied since this is a canonical splice site variant.

PP1

This variant was not found to co-segregate with disease in 3 or more affected family members in the literature.

PP3

This rule cannot be applied since this is a canonical splice site variant.

PP2

The MMVCEP does not evaluate this rule.

PP4

The MMVCEP does not evaluate this rule.

Approved on: 2023-12-09

Published on: 2023-12-09

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