VCV002092471.3 - ClinVar

NM_001754.5(RUNX1):c.385_395del (p.Leu129fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

2 submissions

2 submitters

2 conditions

Reviewed by expert panel

Likely Pathogenic

Sep 2024 by ClinGen Myeloi… FDA Recognized Database

for Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001754.5(RUNX1):c.385_395del (p.Leu129fs)

Variation ID: 2092471 Accession: VCV002092471.3

Type and length

Deletion, 11 bp

Location

Cytogenetic: 21q22.12 21: 34880670-34880680 (GRCh38) [ NCBI UCSC ] 21: 36252967-36252977 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Sep 16, 2024	Sep 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001754.5:c.385_395del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001745.2:p.Leu129fs	frameshift
NM_001001890.3:c.304_314del	NP_001001890.1:p.Leu102fs	frameshift
NM_001122607.2:c.304_314del	NP_001116079.1:p.Leu102fs	frameshift
NC_000021.9:g.34880671_34880681del
NC_000021.8:g.36252968_36252978del
NG_011402.2:g.1109032_1109042del
LRG_482:g.1109032_1109042del
LRG_482t1:c.384_394del	LRG_482p1:p.Leu129Aspfs

... more HGVS ... less HGVS

Protein change

L129fs, L102fs

Other names

NM_001754.5(RUNX1):c.385_395del
p.Leu129fs

Canonical SPDI

NC_000021.9:34880669:ACAGTGACCAGA:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RUNX1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1261	1623
RUNX1-AS1	-	-	-	GRCh38	-	316

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	Pathogenic (1)	criteria provided, single submitter	Feb 3, 2022	RCV002996576.3
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	Likely pathogenic (1)	reviewed by expert panel	Sep 10, 2024	RCV004700884.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely Pathogenic (Sep 10, 2024)	reviewed by expert panel (ClinGen MyeloMalig ACMG Specifications v2) Method: curation	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Myeloid Malignancy Variant Curation Expert Panel FDA Recognized Database Accession: SCV005205697.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2714a8bd-0723-4a2e-b00a-8527d6936038 Comment: NM_001754.5(RUNX1):c.385_395del (p.Leu129AspfsTer5) is a frameshift variant that occurs which terminates 5 amino acids downstream and is predicted to undergo NMD (As per modified RUNX1 PVS1 … (more) NM_001754.5(RUNX1):c.385_395del (p.Leu129AspfsTer5) is a frameshift variant that occurs which terminates 5 amino acids downstream and is predicted to undergo NMD (As per modified RUNX1 PVS1 decision tree ) (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. (less)
Pathogenic (Feb 03, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003313580.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 18723428‚ 24100448 Comment: This sequence change creates a premature translational stop signal (p.Leu129Aspfs5) in the RUNX1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu129Aspfs5) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). (less)

Comment:

NM_001754.5(RUNX1):c.385_395del (p.Leu129AspfsTer5) is a frameshift variant that occurs which terminates 5 amino acids downstream and is predicted to undergo NMD (As per modified RUNX1 PVS1 decision tree ) (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting.

Comment:

This sequence change creates a premature translational stop signal (p.Leu129Aspfs*5) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects.	Stockley J	Blood	2013	PMID: 24100448
Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy.	Owen CJ	Blood	2008	PMID: 18723428
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2714a8bd-0723-4a2e-b00a-8527d6936038	-	-	-	-

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001754.5(RUNX1):c.385_395del (p.Leu129fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...