VCV003343281.2 - ClinVar

NM_001754.5(RUNX1):c.388G>C (p.Val130Leu)

Germline

Top reviewed classifications are shown here.

Submission summary:

2 submissions

2 submitters

2 conditions

Reviewed by expert panel

Uncertain Significance

Oct 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.388G>C (p.Val130Leu)

Variation ID: 3343281 Accession: VCV003343281.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.12 21: 34880677 (GRCh38) [ NCBI UCSC ] 21: 36252974 (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	Oct 8, 2024	Nov 3, 2024	Oct 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001754.5:c.388G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001745.2:p.Val130Leu	missense
NM_001001890.3:c.307G>C	NP_001001890.1:p.Val103Leu	missense
NM_001122607.2:c.307G>C	NP_001116079.1:p.Val103Leu	missense
NC_000021.9:g.34880677C>G
NC_000021.8:g.36252974C>G
NG_011402.2:g.1109035G>C
LRG_482:g.1109035G>C
LRG_482t1:c.388G>C	LRG_482p1:p.Val130Leu

... more HGVS ... less HGVS

Protein change

V103L, V130L

Other names

NM_001754.5:c.388G>C

Canonical SPDI

NC_000021.9:34880676:C:G

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	1265	1627
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.
not provided	Uncertain significance (1)	criteria provided, single submitter	May 5, 2023	RCV004726100.1
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	Uncertain significance (1)	reviewed by expert panel	Oct 29, 2024	RCV004775632.1

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.
Uncertain Significance (Oct 29, 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: SCV005382779.1 First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6ecb3aae-2f4b-4dbf-b91e-b3fa2efc1423 Comment: NM_001754.5(RUNX1):c.388G>C (p.Val130Leu) is a missense variant which has a REVEL score ≥ 0.88 (0.915) (PP3). This variant affects a residue within the Runt Homology Domain … (more) NM_001754.5(RUNX1):c.388G>C (p.Val130Leu) is a missense variant which has a REVEL score ≥ 0.88 (0.915) (PP3). This variant affects a residue within the Runt Homology Domain (AA 89-204) but does not affect an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. (less)
Uncertain significance (May 05, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005334216.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)

Comment:

NM_001754.5(RUNX1):c.388G>C (p.Val130Leu) is a missense variant which has a REVEL score ≥ 0.88 (0.915) (PP3). This variant affects a residue within the Runt Homology Domain (AA 89-204) but does not affect an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6ecb3aae-2f4b-4dbf-b91e-b3fa2efc1423	-	-	-	-

Text-mined citations for this variant ...

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_001754.5(RUNX1):c.388G>C (p.Val130Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...