VCV001028620.3 - ClinVar

NM_000215.4(JAK3):c.1108G>A (p.Glu370Lys)

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity 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.

Uncertain significance

criteria provided, single submitter

Variant Details

Identifiers

NM_000215.4(JAK3):c.1108G>A (p.Glu370Lys)

Variation ID: 1028620 Accession: VCV001028620.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.11 19: 17841423 (GRCh38) [ NCBI UCSC ] 19: 17952232 (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	Mar 22, 2021	Feb 7, 2023	Aug 23, 2022
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000215.4:c.1108G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000206.2:p.Glu370Lys	missense
NC_000019.10:g.17841423C>T
NC_000019.9:g.17952232C>T
NG_007273.1:g.11569G>A
LRG_77:g.11569G>A
LRG_77t1:c.1108G>A

... more HGVS ... less HGVS

Protein change

E370K

Other names

Canonical SPDI

NC_000019.10:17841422: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.

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

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs200631515 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.
JAK3		-	-	GRCh38 GRCh37	1232	1245

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.
T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 23, 2022	RCV001329704.3

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 (Dec 16, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	T-B+ severe combined immunodeficiency due to JAK3 deficiency Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001521216.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Aug 23, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	T-B+ severe combined immunodeficiency due to JAK3 deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003276264.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 370 of the JAK3 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 370 of the JAK3 protein (p.Glu370Lys). This variant is present in population databases (rs200631515, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with JAK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1028620). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 370 of the JAK3 protein (p.Glu370Lys). This variant is present in population databases (rs200631515, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with JAK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1028620). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Uncertain significance criteria provided, single submitter	Jul 31, 2024	RCV004671344.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity 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)	Tumor type Help The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Uncertain significance

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094006.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs200631515 ...

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_000215.4(JAK3):c.1108G>A (p.Glu370Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs200631515 ...