VCV000931873.4 - ClinVar

NM_001754.5(RUNX1):c.1277_1278insCCCCCCCCCCC (p.Arg427fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

2 submissions

2 submitters

2 conditions

Reviewed by expert panel

Likely Pathogenic

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.1277_1278insCCCCCCCCCCC (p.Arg427fs)

Variation ID: 931873 Accession: VCV000931873.4

Type and length

Insertion, 11 bp

Location

Cytogenetic: 21q22.12 21: 34792300-34792301 (GRCh38) [ NCBI UCSC ] 21: 36164597-36164598 (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	Jul 4, 2020	Sep 16, 2024	Aug 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001754.5:c.1277_1278insCCCCCCCCCCC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001745.2:p.Arg427fs	frameshift
NM_001001890.3:c.1196_1197insCCCCCCCCCCC	NP_001001890.1:p.Arg400fs	frameshift
NC_000021.9:g.34792302_34792303insGGGGGGGGGGG
NC_000021.8:g.36164599_36164600insGGGGGGGGGGG
NG_011402.2:g.1197411_1197412insCCCCCCCCCCC
LRG_482:g.1197411_1197412insCCCCCCCCCCC
LRG_482t1:c.1277_1278insCCCCCCCCCCC

... more HGVS ... less HGVS

Protein change

R427fs, R400fs

Other names

NM_001754.5(RUNX1):c.1277_1278insCCCCCCCCCCC
p.Arg427fs

Canonical SPDI

NC_000021.9:34792300:GG:GGGGGGGGGGGGG

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

dbSNP: rs2056451263 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

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	Benign (1)	criteria provided, single submitter	Oct 19, 2018	RCV001198837.2
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	Likely pathogenic (1)	reviewed by expert panel	Aug 28, 2024	RCV004699188.1

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 (Aug 28, 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: SCV005205638.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/41b15e95-a09a-4f42-97bf-6ddbb6576d89 Comment: NM_001754.5(RUNX1):c.1277_1278insCCCCCCCCCCC (p.Arg427ProfsTer?) is an insertion that results in a frameshift. This frameshift variant is located downstream of c.98 (PM5_Supporting). It is not predicted to undergo … (more) NM_001754.5(RUNX1):c.1277_1278insCCCCCCCCCCC (p.Arg427ProfsTer?) is an insertion that results in a frameshift. This frameshift variant is located downstream of c.98 (PM5_Supporting). It is not predicted to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.780-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets 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)
Benign (Oct 19, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369832.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2.

Comment:

NM_001754.5(RUNX1):c.1277_1278insCCCCCCCCCCC (p.Arg427ProfsTer?) is an insertion that results in a frameshift. This frameshift variant is located downstream of c.98 (PM5_Supporting). It is not predicted to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.780-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets 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.

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/41b15e95-a09a-4f42-97bf-6ddbb6576d89	-	-	-	-

Text-mined citations for rs2056451263 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001754.5(RUNX1):c.1277_1278insCCCCCCCCCCC (p.Arg427fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2056451263 ...