VCV003336850.1 - ClinVar

NM_001754.5(RUNX1):c.484_485delinsGC (p.Arg162Ala)

Germline

Top reviewed classifications are shown here.

Submission summary:

1 submission

1 submitter

1 condition

Reviewed by expert panel

Uncertain Significance

Aug 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.484_485delinsGC (p.Arg162Ala)

Variation ID: 3336850 Accession: VCV003336850.1

Type and length

Indel, 2 bp

Location

Cytogenetic: 21q22.12 21: 34880580-34880581 (GRCh38) [ NCBI UCSC ] 21: 36252877-36252878 (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	Aug 18, 2024	Aug 18, 2024	Aug 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001754.5:c.484_485delinsGC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001745.2:p.Arg162Ala	missense
NM_001001890.3:c.403_404delinsGC	NP_001001890.1:p.Arg135Ala	missense
NM_001122607.2:c.403_404delinsGC	NP_001116079.1:p.Arg135Ala	missense
NC_000021.9:g.34880580_34880581delinsGC
NC_000021.8:g.36252877_36252878delinsGC
NG_011402.2:g.1109131_1109132delinsGC
LRG_482:g.1109131_1109132delinsGC
LRG_482t1:c.484_485delAGinsGC	LRG_482p1:p.Arg162Ala

... more HGVS ... less HGVS

Protein change

R135A, R162A

Other names

NM_001122607.2:c.403_404delinsGC

Canonical SPDI

NC_000021.9:34880579:CT:GC

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 hematologic cancer predisposition syndrome	Uncertain significance (1)	reviewed by expert panel	Aug 16, 2024	RCV004696629.1

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 (Aug 16, 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: SCV005196488.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024	Publications: PubMed (8) PubMed: 12807882‚ 19808697‚ 11276260‚ 12377125‚ 27294619‚ 12393679‚ 28231333‚ 23958918 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2a550576-958a-4225-ac13-e4f4abd6c845 Comment: NM_001754.5(RUNX1):c.484_485delinsGC (p.Arg162Ala) is a missense variant which has not been reported in gnomAD (v2 and v3) (PM2_supporting) or in case reports. However, it is located … (more) NM_001754.5(RUNX1):c.484_485delinsGC (p.Arg162Ala) is a missense variant which has not been reported in gnomAD (v2 and v3) (PM2_supporting) or in case reports. However, 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). Transactivation studies are not available for the variant, but it has been associated with decreased DNA-binding only (PMID: 12807882, 11276260, 9533875). The missense variant's REVEL score is not available, but other computational evidence supports a deleterious effect for 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 a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PM5_supporting, and PP3. (less)

Comment:

NM_001754.5(RUNX1):c.484_485delinsGC (p.Arg162Ala) is a missense variant which has not been reported in gnomAD (v2 and v3) (PM2_supporting) or in case reports. However, 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). Transactivation studies are not available for the variant, but it has been associated with decreased DNA-binding only (PMID: 12807882, 11276260, 9533875). The missense variant's REVEL score is not available, but other computational evidence supports a deleterious effect for 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 a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PM5_supporting, and PP3.

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
Molecular mechanisms of cooperative binding of transcription factors Runx1-CBFβ-Ets1 on the TCRα gene enhancer.	Kasahara K	PloS one	2017	PMID: 28231333
Protein-structure-guided discovery of functional mutations across 19 cancer types.	Niu B	Nature genetics	2016	PMID: 27294619
Monitoring of residual disease by next-generation deep-sequencing of RUNX1 mutations can identify acute myeloid leukemia patients with resistant disease.	Kohlmann A	Leukemia	2014	PMID: 23958918
AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations.	Tang JL	Blood	2009	PMID: 19808697
Energetic contribution of residues in the Runx1 Runt domain to DNA binding.	Li Z	The Journal of biological chemistry	2003	PMID: 12807882
Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia.	Harada H	Blood	2003	PMID: 12393679
DNA recognition by the RUNX1 transcription factor is mediated by an allosteric transition in the RUNT domain and by DNA bending.	Bartfeld D	Structure (London, England : 1993)	2002	PMID: 12377125
The leukemia-associated AML1 (Runx1)--CBF beta complex functions as a DNA-induced molecular clamp.	Bravo J	Nature structural biology	2001	PMID: 11276260
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2a550576-958a-4225-ac13-e4f4abd6c845	-	-	-	-

Text-mined citations for this variant ...

Record last updated Aug 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001754.5(RUNX1):c.484_485delinsGC (p.Arg162Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...