VCV000134542.17 - ClinVar

NM_002227.4(JAK1):c.1951G>A (p.Val651Met)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002227.4(JAK1):c.1951G>A (p.Val651Met)

Variation ID: 134542 Accession: VCV000134542.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.3 1: 64846685 (GRCh38) [ NCBI UCSC ] 1: 65312368 (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	Jun 9, 2014	Nov 24, 2024	Sep 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002227.4:c.1951G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002218.2:p.Val651Met	missense
NM_001320923.2:c.1951G>A	NP_001307852.1:p.Val651Met	missense
NM_001321852.2:c.1951G>A	NP_001308781.1:p.Val651Met	missense
NM_001321853.2:c.1951G>A	NP_001308782.1:p.Val651Met	missense
NM_001321854.2:c.1951G>A	NP_001308783.1:p.Val651Met	missense
NM_001321855.2:c.1951G>A	NP_001308784.1:p.Val651Met	missense
NM_001321856.2:c.1951G>A	NP_001308785.1:p.Val651Met	missense
NM_001321857.2:c.1948G>A	NP_001308786.1:p.Val650Met	missense
NC_000001.11:g.64846685C>T
NC_000001.10:g.65312368C>T
NG_023402.2:g.226062G>A
LRG_1398:g.226062G>A
LRG_1398t1:c.1951G>A	LRG_1398p1:p.Val651Met

... more HGVS ... less HGVS

Protein change

V651M, V650M

Other names

p.Val651Met

Canonical SPDI

NC_000001.11:64846684:C:T

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.

0.00100 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00081

Exome Aggregation Consortium (ExAC) 0.00088

Trans-Omics for Precision Medicine (TOPMed) 0.00092

The Genome Aggregation Database (gnomAD) 0.00093

1000 Genomes Project 0.00100

1000 Genomes Project 30x 0.00125

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00164

Links

ClinGen: CA160140 dbSNP: rs149968614 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.
JAK1		-	-	GRCh38 GRCh37	529	623
LOC126805749	-	-	-	GRCh38	-	54

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 specified	not provided (1)	no classification provided	Sep 19, 2013	RCV000121231.1
not provided	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Sep 3, 2024	RCV001725975.15
Autoinflammation, immune dysregulation, and eosinophilia	Uncertain significance (1)	criteria provided, single submitter	Aug 31, 2021	RCV002055339.1

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 31, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammation, immune dysregulation, and eosinophilia Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV002495810.1 First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022	Comment: JAK1 NM_002227.4 exon 14 p.Val651Met (c.1951G>A): This variant has not been reported in the literature but is present in 0.1% (34/30580) of South Asian alleles, … (more) JAK1 NM_002227.4 exon 14 p.Val651Met (c.1951G>A): This variant has not been reported in the literature but is present in 0.1% (34/30580) of South Asian alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-65312368-C-T?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Likely benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002287677.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005186737.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024
Uncertain significance (Jan 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004700363.8 First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (Sep 03, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005408061.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (3) PubMed: 21537335‚ 33489052‚ 37287455 Comment: BS2, PP2 Number of individuals with the variant: 3
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001962840.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001970739.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085402.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic

Comment:

JAK1 NM_002227.4 exon 14 p.Val651Met (c.1951G>A): This variant has not been reported in the literature but is present in 0.1% (34/30580) of South Asian alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-65312368-C-T?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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
Venetoclax durable response in adult relapsed/refractory Philadelphia-negative acute lymphoblastic leukemia with JAK/STAT pathway alterations.	Ferrari A	Frontiers in cell and developmental biology	2023	PMID: 37287455
The Importance of Targeted Next-Generation Sequencing Usage in Cytogenetically Normal Myeloid Malignancies.	Atli EI	Mediterranean journal of hematology and infectious diseases	2021	PMID: 33489052
Frequency and prognostic implications of JAK 1-3 aberrations in Down syndrome acute lymphoblastic and myeloid leukemia.	Blink M	Leukemia	2011	PMID: 21537335

Text-mined citations for rs149968614 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_002227.4(JAK1):c.1951G>A (p.Val651Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs149968614 ...